Chemokine receptor binding heterocyclic compounds

ABSTRACT

Compounds which modulate chemokine receptor activities are disclosed. These compounds are preferably tertiary amines comprising tetrahydroquinoline and benzimidazole.

[0001] This application claims priority under 35 U.S.C. 119(e) fromProvisional Application No. 60/232,891 filed Sep. 15, 2000; No.60/234,510 filed Sep. 22, 2000; Application No. 60/233,087 filed Sep.15, 2000; and Application No. 60/234,816 filed Sep. 22, 2000. Thecontents of these applications are incorporated herein by reference.

TECHNICAL FIELD

[0002] This invention generally relates to novel compounds,pharmaceutical compositions and their use. This invention morespecifically relates to novel heterocyclic compounds that bind tochemokine receptors, including CXCR4 and CCR5, and demonstrateprotective effects against infection of target cells by a humanimmunodeficiency virus (HIV).

BACKGROUND OF THE INVENTION

[0003] Approximately 40 human chemokines have been described, thatfunction, at least in part, by modulating a complex and overlapping setof biological activities important for the movement of lymphoid cellsand extravasation and tissue infiltration of leukocytes in response toinciting agents (See, for example: P. Ponath, Exp. Opin. Invest. Drugs,7:1-18, 1998; Baggiolini, M. Nature 392, 565-568 (1998); Locati et al.Annu. Rev. Med. 50, 425-40 (1999)). These chemotactic cytokines, orchemokines, constitute a family of proteins, approximately 8-10 kDa insize. Chemokines appear to share a common structural motif, thatconsists of 4 conserved cysteines involved in maintaining tertiarystructure. There are two major subfamilies of chemokines: the “CC” orβ-chemokines and the “CXC” or α-chemokines. The receptors of thesechemokines are classified based upon the chemokine that constitutes thereceptor's natural ligand. Receptors of the β-chemokines are designated“CCR” while those of the α-chemokines are designated “CXCR”.

[0004] Chemokines are considered to be principal mediators in theinitiation and maintenance of inflammation (see Chemokines in Diseasepublished by Humana Press (1999), Edited by C. Herbert; Murdoch et al.Blood 95, 3032-3043 (2000)). More specifically, chemokines have beenfound to play an important role in the regulation of endothelial cellfunction, including proliferation, migration and differentiation duringangiogenesis and re-endothelialization after injury (Gupta et al., J.Biol. Chem., 7:4282-4287 (1998); Volin et al Biochem. Biophys Res.Commun. 242, 46-53 (1998)). Two specific chemokines have been implicatedin the etiology of infection by human innunodeficiency virus (HIV).

[0005] In most instances, HIV initially binds via its gp120 envelopeprotein to the CD4 receptor of the target cell. A conformational changeappears to take place in gp120 which results in its subsequent bindingto a chemokine receptor, such as CCR5 (Wyatt et al., Science,280:1884-1888 (1998); Rizzuto et al. Science, 280:1949-1953 (1998);Berger et al. Annu. Rev. Immunol. 17: 657-700 (1999)). HIV-1 isolatesarising subsequently in the infection bind to the CXCR4 chemokinereceptor.

[0006] Following the initial binding by HIV to CD4, virus-cell fusionresults, which is mediated by members of the chemokine receptor family,with different members serving as fusion cofactors for macrophage-tropic(M-tropic) and T cell line-tropic (T-tropic) isolates of HIV-1 (Carrollet al., Science, 276: 273-276 1997; Feng et al. Science 272, 872-877(1996); Bleul et al. Nature 382, 829-833 (1996); Oberlin et al. Nature382, 833-835 (1996); Cocchi et al. Science 270, 1811-1815 (1995); Dragicet al. Nature 381, 667-673 (1996); Deng et al. Nature 381, 661-666(1996); Alkhatib et al. Science 272, 1955-1958, 1996). During the courseof infection within a patient, it appears that a majority of HIVparticles shift from the M-tropic to the more pathogenic T-tropic viralphenotype (Blaak et al. Proc. Natl. Acad. Sci. 97, 1269-1274 (2000);Miedema et al., Immune. Rev., 140:35 (1994); Simmonds et al. J. Virol.70, 8355-8360 (1996); Tersmette et al. J. Virol. 62, 2026-2032, 1988);Connor, R. I., Ho, D. D. J. Virol. 68, 4400-4408 (1994); Schuitemaker etal. J. Virol. 66, 1354-1360 (1992)). The M-tropic viral phenotypecorrelates with the virus's ability to enter the cell following bindingof the CCR5 receptor, while the T-tropic viral phenotype correlates withviral entry into the cell following binding and membrane fusion with theCXCR4 receptor. Clinical observations suggest that patients who possessgenetic mutations in CCR5 appear resistant, or less susceptible to HIVinfection (Liu et al. Cell 86, 367-377 (1996); Samson et al. Nature 382,722-725 (1996); Michael et al. Nature Med. 3, 338-340 (1997); Michael etal. J. Virol. 72, 6040-6047 (1998); Obrien et al. Lancet 349, 1219(1997); Zhang et al. AIDS Res. Hum. Retroviruses 13, 1357-1366 (1997);Rana et al. J. Virol. 71, 3219-3227 (1997); Theodorou et al. Lancet 349,1219-1220 (1997). Despite the number of chemokine receptors which havebeen reported to HIV mediate entry into cells, CCR5 and CXCR4 appear tobe the only physiologically relevant coreceptors used by a wide varietyof primary clinical HIV-1 strains (Zhang et al. J. Virol. 72, 9307-9312(1998); Zhang et al. J. Virol. 73, 3443-3448 (1999); Simmonds et al. J.Virol. 72, 8453-8457 (1988)). Fusion and entry of T-tropic viruses thatuse CXCR4 are inhibited by the natural CXC-chemokine stromalcell-derived factor-1, whereas fusion and entry of M-tropic viruses thatuse CCR5 are inhibited by the natural CC-chemokines namely, Regulated onActivation Normal T-cell Expressed and Secreted (RANTES) and MacrophageInflammatory proteins (MIP-1 alpha and beta).

[0007] In addition to serving as a co-factor for HIV entry, the directinteraction of virus-associated gp120 with CXCR4 has been recentlysuggested as a possible cause of CD8³⁰ T-cell apoptosis and AIDS-relateddementia via induction of neuronal cell apoptosis (Hesselgesser et al.Curr. Biol. 8, 595-598 (1998); Hesselgesser et al. Curr. Biol. 7,112-121 (1997); Hesselgesser et al. “Chemokines and Chemokine receptorsin the Brain” in Chemokines in Disease published by Humana Press (1999),Edited by C. Herbert; Herbein et al. Nature 395, 189-194 (1998); Buttiniet al. Nature Med. 4, 441-446 (1998); Ohagen et al. J. Virol. 73,897-906 (1999); Biard-Piechaczyk et al. Virology 268, 329-344 (2000);Sanders et al. J. Neuroscience Res. 59, 671-679 (2000); Bajetto et al.J. Neurochem. 73, 2348-2357 (1999); Zheng et al. J. Virol. 73, 8256-8267(1999)).

[0008] However, the binding of chemokine receptors to their naturalligands appears to serve a more evolutionary and central role than onlyas mediators of HIV infection. The binding of the natural ligand,pre-B-cell growth-stimulating factor/stromal cell derived factor(PBSF/SDF-1) to the CXCR4 chemokine receptor provides an importantsignaling mechanism: CXCR4 or SDF-1 knock-out mice exhibit cerebellar,cardiac and gastrointestinal tract abnormalities and die in utero (Zouet al., Nature, 393:591-594 (1998); Tachibana et al., Nature,393:591-594 (1998); Nagasawa et al. Nature 382, 635-638 (1996)).CXCR4-deficient mice also display hematopoietic defects (Nagasawa et al.Nature 382, 635-638 (1996)); the migration of CXCR4 expressingleukocytes and hematopoietic progenitors to SDF-1 appears to beimportant for maintaining B-cell lineage and localization of CD34⁺progenitor cells in bone marrow (Bleul et al. J. Exp. Med. 187, 753-762(1998); Viardot et al. Ann. Hematol. 77, 195-197 (1998); Auiti et al. J.Exp. Med. 185, 111-120 (1997); Peled et al. Science 283, 845-848 (1999);Qing et al. Immunity 10, 463-471 (1999); Lataillade et al. Blood 95,756-768 (1999); Ishii et al. J. Immunol. 163, 3612-3620 (1999); Maekawaet al. Internal Medicine 39, 90-100 (2000); Fedyk et al. J. LeukocyteBiol. 66, 667-673 (1999); Peled et al. Blood 95, 3289-3296 (2000)).

[0009] The signal provided by SDF-1 on binding to CXCR4 may also play animportant role in tumor cell proliferation and regulation ofangiogenesis associated with tumor growth (See “Chemokines and Cancer”published by Humana Press (1999); Edited by B. J. Rollins; Arenburg etal. J. Leukocyte Biol. 62, 554-562 (1997); Moore et al. J. Invest. Med.46, 113-120 (1998); Moore et al. Trends cardiovasc. Med. 8, 51-58(1998); Seghal et al. J. Surg. Oncol. 69, 99-104 (1998)); the knownangiogenic growth factors VEG-F and bFGF, up-regulate levels of CXCR4 inendothelial cells, and SDF-1 can induce neovascularization in vivo(Salcedo et al. Am. J. Pathol. 154, 1125-1135 (1999)); Leukemia cellsthat express CXCR4 migrate and adhere to lymph nodes and bone marrowstromal cells that express SDF-1 (Burger et al. Blood 94, 3658-3667(1999); Arai et al. Eur. J. Haematol. 64, 323-332 (2000); Bradstock etal. Leukemia 14, 882-888 (2000)).

[0010] The binding of SDF-1 to CXCR4 has also been implicated in thepathogenesis of atherosclerosis (Abi-Younes et al. Circ. Res. 86,131-138 (2000)), renal allograft rejection (Eitner et al.Transplantation 66, 1551-1557 (1998)), asthma and allergic airwayinflammation (Yssel et al. Clinical and Experimental Allergy 28, 104-109(1998); J. Immunol. 164, 5935-5943 (2000); Gonzalo et al. J. Immunol.165, 499-508 (2000)), Alzheimers disease (xia et al. J. Neurovirology 5,32-41 (1999)) and Arthritis (Nanki et al. J. Immunol. 164, 5010-5014(2000)).

[0011] In attempting to better understand the relationship betweenchemokines and their receptors, recent experiments to block the fusion,entry and replication of HIV via the CXCR4 chemokine receptor werecarried out through the use of monoclonal antibodies or small moleculesthat appear to suggest a useful therapeutic strategy (Schols et al., J.Exp. Med. 186:1383-1388 (1997); Schols et al., Antiviral Research35:147-156 (1997); Bridger et al. J. Med. Chem. 42, 3971-3981 (1999);Bridger et al. “Bicyclam Derivatives as HIV Inhibitors” in Advances inAntiviral Drug Design Volume 3, p161-229; Published by JAI press (1999);Edited by E. De Clercq). Small molecules, such as bicyclams, appear tospecifically bind to CXCR4 and not CCR5 (Donzella et al., NatureMedicine, 4:72-77 (1998)). These experiments demonstrated interferencewith HIV entry and membrane fusion into the target cell in vitro. Morerecently, bicyclams were also shown to inhibit fusion and replication ofFeline Immunodeficiency Virus (FIV) that uses CXCR4 for entry (Egberinket al. J. Virol. 73, 6346-6352 (1999)).

[0012] Additional experiments have shown that the bicyclamdose-dependently inhibits binding of 125I-labeled SDF-1 to CXCR4 and thesignal transduction (indicated by an increase in intracellular calcium)in response to SDF-1. Thus, the bicyclam also functioned as anantagonist to the signal transduction resulting from the binding ofstromal derived factor or SDF-1α, the natural chemokine to CXCR4.Bicyclams also inhibited HIV gp120 (envelope)-induced apoptosis innon-HIV infected cells (Blanco et al. Antimicrobial Agents andChemother. 44, 51-56 (2000)).

[0013] U.S. Pat. Nos. 5,583,131; 5,698,546; 5,817,807; 5,021,409; and6,001,826 which are herein incorporated in their entirety by reference,disclose cyclic compounds that are active against HIV-1 and HIV-2 in invitro tests. It was subsequently discovered and further disclosed incopending application U.S. Ser. No. 09/111,895 and U.S. Serial No.60/172,153 that these compounds exhibit anti-HIV activity by binding tothe chemokine receptor CXCR4 expressed on the surface of certain cellsof the immune system. This competitive binding thereby protects thesetarget cells from infection by HIV which utilize the CXCR4 receptor forentry. In addition, these compounds antagonize the binding, signalingand chemotactic effects of the natural ligand for CXCR4, the chemokinestromal cell-derived factor 1α (SDF-1). We further disclosed that thesenovel compounds demonstrate protective effects against HIV infection oftarget cells by binding in vitro to the CCR5 receptor.

[0014] Additionally we have disclosed in U.S. Ser. No. 09/495,298 thatthese cyclic polyamine antiviral agents described in the above-mentionedpatents have the effect of enhancing production of white blood cells aswell as exhibiting antiviral properties. Thus, these agents are usefulfor controlling the side-effects of chemotherapy, enhancing the successof bone marrow transplantation, enhancing wound healing and burntreatment, as well as combating bacterial infections in leukemia.

[0015] More recently, we disclosed in U.S. Ser. No. 09/535,314, a seriesof heterocyclic compounds that exhibit anti-HIV activity by binding tothe chemokine receptors CXCR4 and CCR5 expressed on the surface ofcertain cells of the immune system. This competitive binding therebyprotects these target cells from infection by HIV which utilize theCXCR4 or CCR5 receptors for entry. In addition, these compoundsantagonize the binding, signaling and chemotactic effects of the naturalligand for CXCR4, the chemokine stromal cell-derived factor 1α (SDF-1)and/or the natural ligand for CCR5, the chemokine RANTES.

[0016] Herein, we disclose novel compounds that exhibit protectiveeffects against HIV infection of target cells by binding to chemokinereceptor CXCR4 or CCR5 in a similar manner to the previously disclosedmacrocyclic compounds. In addition, these compounds antagonize thebinding, signaling and chemotactic effects of the natural ligand forCXCR4, the chemokine stromal cell-derived factor 1α (SDF-1) and/or thenatural ligand for CCR5, the chemokine RANTES.

[0017] Citation of the above documents is not intended as an admissionthat any of the foregoing is pertinent prior art. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents. Further, all documents referred to throughout thisapplication are hereby incorporated in their entirety by referenceherein.

SUMMARY OF THE INVENTION

[0018] The present invention provides novel compounds that bindchemokine receptors and interfere with the binding of the natural ligandthereto. The compounds of the present invention are useful as agentsdemonstrating protective effects on target cells from HIV infection.Other embodiments of the present invention are compounds that act asantagonists or agonists of chemokine receptors, as well as otherbiological activities related to the ability of these compounds toinhibit the binding of chemokines to their receptors.

[0019] The compounds of the invention are of Formula (1), including thepharmaceutically acceptable salts and pro-drug forms thereof. Thecompounds of Formula (1) are of the formula:

[0020] wherein:

[0021] Ring A optionally comprises a heteroatom selected from N, O andS;

[0022] the dotted lines represent optional unsaturation;

[0023] R¹, R² and R³ are non-interfering substituents;

[0024] k is 0-4;

[0025] l is 0, 1, or 2;

[0026] X is unsubstituted or substituted C or N; or is O or S;

[0027] Ar is the residue of an aromatic or heteroarmatic moiety;

[0028] each n is independently 0-2;

[0029] each R is independently H or alkyl (1-6C);

[0030] j is 0-3; and

[0031] each Y is independently an optional substituent, as definedherein other than CR₂NR(CR₂)_(n)B where B is aromatic or heteroaromaticor other heterocycle.

[0032] Preferably, each Y is independently halo, OH, SH, SO, SO₂, or anorganic moiety of 1-20C atoms that does not contain N wherein two such Ymay be connected to form a fused ring wth Ar, or is selected from thegroup consisting of

[0033] —(CR₂)_(m)CN,

[0034] —(CR₂)_(m)NR⁵ ₂,

[0035] —(CR₂)_(m)NR(CR₂)_(m)NRR⁴,

[0036] —(CR₂)_(m)NR(CR₂)_(m)NR(CR₂)_(m)NR⁵ ₂,

[0037] —(CR₂)_(m)CO(CR₂)_(m)NR⁵ ₂,

[0038] —(CR₂)_(m)CO(CR₂)_(m)NR(CR₂)_(m)NRR⁴,

[0039] —(CR₂)_(m)CO(CR₂)_(m)NR(CR₂)_(m)NR(CR₂)_(m)NR⁵ ₂,

[0040] —(CR₂)_(m)NRCO(CR₂)_(m)NRR⁴,

[0041] —(CR₂)_(m)NRCO(CR₂)_(m)NR(CR₂)_(m)NR⁵ ₂,

[0042] —(CR₂)_(m)NRCO(CR₂)_(m)NR(CR₂)_(m)NR(CR₂)_(m)NR(CR₂)_(m)NR⁵ ₂,

[0043] —CH═N—Z,

[0044] —(CR₂)_(m)Z,

[0045] —NR (CR₂)_(m)Z,

[0046] —(CR₂)_(m)NROH,

[0047] (CR₂)_(m)CONROH, and

[0048] (CR₂)_(m)CR═NOH,

[0049] and those wherein Y comprises guanidino or NHNHR, or amidino;

[0050] wherein Z is an optionally substituted aromatic or heteroaromaticmoiety containing 5-12 ring members; and

[0051] wherein R is as defined above, each m is independently 0-4, andR⁴ and each R⁵ is independently H, alkyl (1-6C), alkenyl (1-6C), alkynyl(1-6C), or acyl (1-6C), each optionally substituted by one or morenonaromatic, nonheterocyclic substituent(s), and wherein two R⁵ may beconnected to form a cyclic amine, optionally containing one or moreadditional heteroatoms selected from N, O, and S.

[0052] The compounds of the invention specifically exclude embodimentswherein Y is CR₂NR(CR₂)_(n)B where B is aromatic or heteroaromatic orother heterocycle.

[0053] The optional substituents are defined infra.

[0054] The invention includes pharmaceutical compositions comprising atherapeutically effective amount of the compound of Formula (1); methodsof treating a disease of the human body or the bodies of other mammalscomprising the administration of such pharmaceutical compositions, and amethod for blocking or interfering with the binding of a chemokinereceptor with its natural ligand, comprising the contacting of saidchemokine receptor with an effective amount of the compound of Formula(1).

[0055] This invention is also directed to use of a compound of Formula(1) in the manufacture of a medicament for the treatment of a disease inwhich blocking or interfering with binding of a chemokine receptor withits natural ligand is advantageous, which method may compriseformulating a composition comprising a therapeutically effective amountof the compound of Formula (1). The invention also provides a method ofprotecting target cells possessing chemokine receptors, the binding towhich by a pathogenic agent results in disease or pathology, comprisingadministering to a mammalian subject a pharmaceutical compositioncomprising a therapeutically effective amount of the compound of Formula(1).

[0056] The compounds of the invention may be tin the form of“pro-drugs”, that is, protected forms of the compounds, which releasethe compound after administration to a patient. For example, thecompound may carry a protective groups which is split off by hydrolysisin body fluids e.g. in the bloodstream, thus releasing active compoundor is oxidized or reduced in body fluids to release the compound. Adiscussion of pro-drugs may be found in “Smith and Williams'Introduction to the Principles of Drug Design”, H. J. Smith, Wright,Second Edition, London 1988.

[0057] Acid addition salts, which are pharmaceutically acceptable, suchas salt with inorganic base, a salt with organic-base, a salt withinorganic acid, a salt with organic acid, a salt with basic or acidicamino acid, etc. are also encompassed in the present invention. Examplesof a salt with an inorganic base include a salt with alkali metal (e.g.sodium, potassium, etc.), alkaline earth metal (e.g. calcium, magnesium,etc.), aluminum, ammonium, etc. Examples of the salt with an organicbase include a salt with trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine, N,N′-dibenzylethylenediamine etc. Examples of thesalt with an inorganic acid include a salt with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.Examples of the salt with an organic acid include a salt with formicacid, oxalic acid, acetic acid, tartaric acid, methanesulfonic acid,benzenesulfonic acid, malic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, etc. Examples of salts with basic aminoacids include a salt with arginine, lysine, ornithine, etc. Examples ofsalts with the acidic amino acid include a salt with aspartic acid,glutamic acid, etc. Non-toxic in the present context has to beconsidered with reference to the prognosis for the infected patientwithout treatment.

MODES OF CARRYING OUT THE INVENTION

[0058] The present invention is directed to compounds of Formula (1)which can act as agents that modulate chemokine receptor activity. Suchchemokine receptors include but are not limited to CCR1, CCR2, CCR3,CCR4, CCR5, CCR6, CCR7, CCR8 and CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5,preferably CXR4 and/or CCR5.

[0059] The compounds affect the binding of a natural ligand or chemokineto a receptor, such as CXCR4 and/or CCR5 of a target cell.

[0060] Thus the compounds affect chemokine receptors, such as CCR1,CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8 and CXCR1, CXCR2, CXCR3, CXCR4and CXCR5 where such chemokine receptors have been correlated as beingimportant mediators of many human inflammatory as well asimmunoregulatory diseases and cancer, and modulate the activity of suchchemokine receptors so as to be useful for the treatment or preventionof such diseases.

[0061] In particular, the compounds of Formula 1 have protective effectson target cells from HIV infection in a manner as to bind specificallyto the chemokine receptor.

[0062] The term “modulators” as used herein is intended to encompassantagonist, agonist, partial antagonist, and or partial agonist,inhibitors, and activators. In the preferred embodiment of the presentinvention, compounds of Formula 1 demonstrate protective effects againstHIV infection by inhibiting the binding of HIV to a chemokine receptorsuch as CXCR4 and/or CCR5 of a target cell. The invention includes amethod which comprises contacting the target cell with an amount of thecompound which is effective at inhibiting binding to the chemokinereceptor.

[0063] The term “therapeutically effective amount” means the amount ofthe subject compound that will elicit a biological or medical responsein a cell, tissue, organ, system, animal or human that is being soughtby the researcher, veterinarian, medical doctor or other clinician.

[0064] The term “administration” and or “administering” of the subjectcompound should be understood to mean as providing a compound of theinvention including a pro-drug of a compound of the invention to theindividual in need of treatment.

[0065] Compounds of the invention that inhibit chemokine receptors maybe used for the treatment both prophylactic and therapeutic of diseasesassociated with hematopoiesis, including but not limited to, controllingthe side-effects of chemotherapy, enhancing the success of bone marrowtransplantation, enhancing wound healing and burn treatment, as well ascombating bacterial infections in leukemia.

[0066] Compounds of the invention that inhibit chemokine receptoractivity and function may be used for the treatment of diseases that areassociated with inflammation, including but are not limited to,inflammatory or allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic pneumonias, delayed-type hypersensitivity, interstitiallung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILDassociated with rheumatoid arthritis, systemic lupus erythematosus,ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome,polymyositis or dermatomyositis); systemic anaphylaxis orhypersensitivity responses, drug allergies, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes;glomerulonephritis, autoimmune throiditis, graft rejection, includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria, vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinphilic myotis, eosiniphilic fascitis; and cancers.

[0067] Compounds of the invention that activate or promote chemokinereceptor function may be used for the treatment of diseases that areassociated with immunosuppression such as individuals undergoingchemotherapy, radiation therapy, enhanced wound healing and burntreatment, therapy for autoimmune disease or other drug therapy (e.g.,corticosteroid therapy) or combination of conventional drugs used in thetreatment of autoimrmune diseases and graft/transplantation rejection,which causes immunosuppression; immunosuppression due to congenitaldeficiency in receptor function or other causes; and infectiousdiseases, such as parasitic diseases, including but not limited tohelminth infections, such as nematodes (round worms); Trichuriasis,Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis,filariasis; trematodes; visceral worms, visceral larva migtrans (e.g.,Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanemassp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostomacaninum); the malaria-causing protozoan Plasmodium vivax, Humancytomegalovirus, Herpesvirus saimiri, and Kaposi's sarcoma herpesvirus,also known as human herpesvirus 8, and poxvirus Moluscum contagiosum.

[0068] One or more compounds of Formula 1 may be used in combinationwith any other pharmaceutical composition where such combined therapymodulates chemokine receptor activity and thereby prevent and treatdiseases associated with hematopoiesis, inflammation, autoimmune,inflammatory dermatoses, cancers, inflammatory bowel diseases, andimmunoregulatory disorders.

[0069] It is also contemplated that the present invention may be used incombinations with one or more agents useful in the prevention ortreatment of HIV. Examples of such agents include:

[0070] (1) nucleotide reverse transcriptase inhibitor such aszidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine,adefovir, adefovir dipivoxil, fozivudine todoxil, etc.;

[0071] (2) non-nucleotide reverse transcriptase inhibitor (including anagent having anti-oxidation activity such as immunocal, oltipraz, etc.)such as nevirapine, delavirdine, efavirenz, loviride, immunocal,oltipraz, etc.; and

[0072] (3) protease inhibitors such as saquinavir, ritonavir, indinavir,nelfinavir, amprenavir, palinavir, lasinavir, etc.

[0073] The scope of combinations of compounds of Formula (1) with HIVagents is not limited to (1), (2), and or (3), but includes inprinciple, any combination with any pharmaceutical composition usefulfor the treatment of HIV. Further, in such combinations the compounds ofthe present invention and other HIV agents may be administeredseparately or in conjunction. In addition, the administration of oneelement may be prior to, concurrent to, or subsequent to theadministration of other agent(s).

[0074] The compounds of Formula (1) may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous,intracistemal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration.

[0075] The compounds of Formula 1 are all active and used to treatanimals, including but not limited to, mice, rats, horses, cattle,sheep, dogs, cats, and monkeys. The compounds of the invention are alsoeffective for use in humans.

[0076] The compounds of Formula 1 may form hydrates or solvates. Thosecompounds of Formula 1 which can exist as regioisomers, configurationalisomers, conformers, or diasteroisomeric forms may occur as mixtures ofsuch forms. Mixtures may be treated so as to isolate individual isomersusing known separation and purification methods, if desired. For examplewhen the compound of Formula (1) is a racemate, it can be separated intothe (S)-compound and (R)-compound by optical resolution. Individualoptical isomers and a mixtures thereof are included in the scope of thepresent invention.

[0077] This invention also relates to a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier or diluent and aneffective amount of compound of Formula 1. A compound of Formula 1 maybe administered alone or as an admixture with a pharmaceuticallyacceptable carrier (e.g. solid formulations such as tablets, capsules,granules, powders, etc.; liquid formulations such as syrups, injections,etc.) may be orally or non-orally administered. Examples of non-oralformulations include injections, drops, suppositories, pessaryies.

[0078] In the treatment or prevention of conditions which requirechemokine receptor modulation an appropriate dosage level will generallybe about 0.01 to 500 mg per kg patient body weight per day which can beadministered in singe or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day. It will be understood thatthe specific dose level and frequency of dosage for any particularpatient may be varied and will depend upon a variety of factorsincluding the activity of the specific compound used, the metabolicstability and length of action of that compound, the age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the particular condition,and the patient undergoing therapy.

[0079] The present invention further provides novel compounds that bindchemokine receptors and interfere with the binding of the natural ligandthereto. The compounds of the present invention are useful as agentsdemonstrating protective effects on target cells from HIV infection. Thecompounds of the present invention are also useful as antagonists oragonists of chemokine receptors, as well as other biological activitiesrelated to the ability of these compounds to inhibit the binding ofchemokines to their receptors.

Further Definition of Substituents

[0080] In the compounds of Formula 1, R may be straight or branchedchain alkyl or may be cyclic, and may optionally be substituted by 1-2substituents selected from halo, hydroxy and alkoxy. Preferably each Ris H or lower straightchain alkyl (1-4C), preferably methyl.

[0081] Ar is the residue of an aromatic or heteroaromatic moiety whichcontains a single or fused ring system and containing 5-6 ring membersin the monocyclic system and 9-12 members in the fused ring system. Theresidue may be optionally substituted. Examples of optionallysubstituted aromatic and heteroaromatic groups include benzene,naphthalene, dihydronaphthalene, tetrahydronaphthalene, pyridine,quinoline, isoquinoline, imidazole, benzimidazole, azabenzimidazole,benzotriazole, furan, benzofuran, thiazole, benzothiazole, oxazole,benzoxazole, pyrrole, indole, imidazole, tetrahydroquinoline,tetrahydroisoquinoline, pyrazole, thiophene, isoxazole, isothiazole,triazole, tetrazole, oxadiazole, thiadiazole, imidazoline, andbenzopyran. Oxides of the nitrogen and sulfur containing heteroaromaticrings are also included in the present invention. Particularly preferredforms of Ar are phenylene, pyridylene or pyridinylene.

[0082] When compounds of Formula (1) contain elements that are“optionally substituted” these substituents are preferably halogen,nitro, cyano, carboxylic acid, optionally substituted alkyl, alkenyl orcycloalkyl groups, an optionally substituted hydroxyl group, anoptionally substituted thiol group, an optionally substituted amino, anoptionally substitute acyl group, an optionally substituted carboxylate,carbamate, carboxamide or sulfonamide group, or an optionallysubstituted aromatic or heterocyclic group.

[0083] Examples of halogen include fluorine, chlorine, bromine, iodine,etc., with fluorine and chlorine preferred.

[0084] Examples of optionally substituted alkyl include C₁₋₁₀ alkyl,including methyl, ethyl propyl etc.; examples of optionally substitutedalkenyl groups include C₂₋₁₀ alkenyl such as allyl, crotyl, 2-pentenyl,3-hexenyl, etc.; and examples of optionally substituted cycloalkylgroups include C₃₋₁₀ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc. In these cases, C₁₋₆ alkyl,alkenyl and cycloalkyl are preferred. The optional substituent may alsobe an optionally substituted aralkyl (e.g. phenyl C₁₋₄ alkyl) orheteroalkyl for example, phenylmethyl (benzyl), phenylethyl,pyridinylmethy, pyridinylethyl, etc. The heterocyclic group may be a 5or 6 membered ring containing 1-4 heteroatoms.

[0085] Examples of optionally substituted hydroxyl and thiol groupsinclude those wherein the substituent is an optionally substituted alkyl(e.g. C₁₋₁₀ alkyl) such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, etc., preferably (C₁₋₆) alkyl;an optionally substituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc., suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);an optionally substituted aralkyl (e.g. phenyl-C₁₋₄ alkyl, e.g. benzyl,phenethyl, etc.). Where there are two adjacent hydroxyl or thiolsubstituents, the heteroatoms may be connected via an alkylene groupsuch as O(CH₂)_(n)O and S(CH₂)_(n)S (where n=1-5). Examples includemethylenedioxy, ethylenedioxy, etc. Oxides of thio-ether groups such assulfoxides and sulfones are also encompassed.

[0086] Further examples of the optionally substituted hydroxyl groupinclude an optionally substituted C₂₋₄ alkanoyl (e.g. acetyl, propionyl,butyryl, isobutyryl, etc.), C₁₋₄ alkylsufonyl (e.g. methanesulfonyl,ethanesulfonyl, etc.) and an optionally substituted aromatic andheterocyclic carbonyl group including benzoyl, pyridinecarbonyl, etc.

[0087] The substituents on optionally substituted amino group may bindto each other to form a cyclic amino group (e.g. 5- to 6-membered cyclicamino, etc., such as tetrahydropyrrole, piperazine, piperidine,pyrrolidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.). Saidcyclic amino group may have a substituent, and examples of thesubstituents include halogen (e.g. fluorine, chlorine, bromine, iodine,etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxylgroup, an optionally halogenated C₁₋₄ alkyl (e.g. trifluoromethyl,methyl, ethyl, etc.), an optionally halogenated C₁₋₄ alkoxy (e.g.methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C₂₋₄ alkanoyl(e.g. acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g.methanesulfonyl, ethanesulfonyl, etc.) the number of preferredsubstituents are 1 to 3.

[0088] The amino group may also be substituted once or twice (to form asecondary or tertiary amine) with a group such as an optionallysubstituted alkyl group including C₁₋₁₀ alkyl (e.g. methyl, ethyl propyletc.); an optionally substituted alkenyl group such as allyl, crotyl,2-pentenyl, 3-hexenyl, etc., or an optionally substituted cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc. In these cases, C₁₋₆ alkyl, alkenyl and cycloalkyl arepreferred. The amine group may also be optionally substituted with anaromatic or heterocyclic group, aralkyl (e.g. phenyl C₁₋₄ alkyl) orheteroalkyl for example, phenyl, pyridine, phenylmethyl (benzyl),phenethyl, pyridinylmethyl, pyridinylethyl etc. The heterocyclic groupmay be a 5 or 6 membered ring containing 1-4 heteroatoms. The optionalsubstituents of the “optionally substituted amino groups are the same asdefined above for the “optionally substituted cyclic amino group.”

[0089] The amino group may be substituted with an optionally substitutedC₂₋₄ alkanoyl e.g. acetyl, propionyl, butyryl, isobutyryl etc., or aC₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.) or acarbonyl or sulfonyl substituted aromatic or heterocyclic ring, e.g.benzenesulfonyl, benzoyl, pyridinesulfonyl, pyridinecarbonyl etc. Theheterocycles are as defined above.

[0090] Examples of the optionally substituted acyl groups include acarbonyl group or a sulfinyl or sulfonyl group binding to hydrogen; orto an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.,preferably lower (C₁₋₆) alkyl, etc.; an optionally substitutedcycloalkyl (e.g. C₃₋₇ cycloalkyl, etc., such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc.); an optionally substitutedalkenyl (e.g. C₂₋₁₀ alkenyl such as allyl, crotyl, 2-pentenyl, etc.,preferably lower (C₂₋₆) alkenyl, etc.); an optionally substitutedcycloalkenyl (e.g. C₃₋₇ cycloalkenyl, etc., such as 2-cyclopentenyl,2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.) anoptionally substituted 5- to 6-membered monocyclic aromatic group (e.g.phenyl, pyridyl, etc.).

[0091] Examples of the optionally substituted carboxylate group (estergroups) include an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆) alkyl, etc.); an optionallysubstituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc. such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); an optionallysubstituted alkenyl (e.g. C₂₋₁₀ alkenyl such as allyl, crotyl,2-pentenyl, 3-hexenyl, etc., preferably lower (C₂₋₆) alkenyl, etc.); anoptionally substituted cycloalkenyl (e.g. C₃₋₇ cycloalkenyl, etc., suchas 2-cyclohexenylmethyl, etc.); an optionally substituted aryl (e.g.phenyl, naphthyl, etc.) and C₁₋₄ aryl for example, benzyl, phenethyletc. Groups such as methoxymethyl, methoxyethyl, etc., are alsoencompassed.

[0092] Examples of the optionally substituted carboxamide andsulfonamide groups are identical in terms of the amine definition as the“optionally substituted amino group” defined above.

[0093] Examples of the optionally substituted aromatic or heterocyclicgroups are phenyl, naphthyl, or a 5- or 6-membered heterocyclic ringcontaining 1-4 heteroatoms. The optional substituents are essentiallyidentical to those listed above.

[0094] The noninterferring substituents R¹, R² and R³ are similar tothose set forth as “optional substituents”. Preferably, R¹ is selectedfrom the optional substituents set forth above, preferably halo,substituted or unsubstituted alkyl, substituted or unsubstitutedhydroxyl, substituted or unsubstituted amino, substituted orunsubstituted thiol, and substituted or unsubstituted acyl. Preferably kis 0-2, preferably 0-1, and more preferably 0.

[0095] The substituents R² and R³ are preferably selected from thepreferred embodiments of R¹ listed immediately above, or, morepreferably, may be joined to form a saturated or unsaturated ringsystem, preferably a benzo ring system.

[0096] In the above Formula 1, examples of the optionally substitutedring system containing ring A are dihydroquinoline, tetrahydroquinoline,pyranopyridine, dihydropyranopyridine, thiapyranopyridine,dihydrothiapyranopyridine, dihydronaphthyridine,tetrahydronaphthyridine. Oxides of sulfur-containing heterocycles arealso encompassed in the present invention. In the above ring systemcontaining Ring A, the optional nitrogen atom may be substituted withhydrogen, a substituted alkyl, alkenyl, cycloalkyl or aryl group, or maybe the nitrogen atom of a carboxamide, carbamate or sulfonamide.Preferred for 1 is l=1, it is preferred that ring A be saturated. Themost preferred combination is tetrahydroquinoline.

[0097] In the above Formula 1, X may be CH (pyrrole), O (oxazole), S(thiazole), NH or NR (imidazole) where R is a C₁₋₆ alkyl group or acyl,sulfonyl group. In Formula 1, two adjacent R¹ and/or R² and R³ may bejoined to form an optionally substituted, fused 5-7 membered ring.Examples of fused ring systems include but are not limited to indole,tetrahydroindole, benzimidazole, tetrahydrobenzimidazole,azabenzimidazole, benzoxazole, tetrahydrobenzoxazole, benzothiazole,tetrahydrobenzothiazole. The preferred ring systems resulting from R²and R³ include those which result in benzothiazole and benzoimidazole.

[0098] In the compounds of Formula 1, it is preferred that one of the(CR₂)_(n) linkers between the ring system containing ring A and ring Eis that wherein n is 0, i.e., the linkage is merely a covalent bond.Also preferred embodiments of (CR₂)_(n) in this context are ethlylene ormethylene, preferrably methylene. In the most preferred embodiments, thelinkage between the nitrogen shown in Formula 1 and ring A is a bond andthat between the nitrogen shown and ring E is CH₂. As shown, ring E maybe coupled to the linker through any position, but preferably throughposition 2, 4 or 5, most preferably through position 2.

[0099] In the compounds of Formula 1, preferred values of j are 0-2,preferrably 1-2. The embodiments of Y may be varied widely provided Ydoes not contain nitrogen. Thus, Y may be halo, OH, SH, SO, SO₂ and thelike, or a substituent of 1-20 carbons, optionally containing as asubstitution, for one or more said carbons, a heteroatom such as O or S.Preferred embodiments wherein N is not present in Y include halo,optionally substituted alkyl, optionally substitued hydroxyl, optionallysubstituted thiol, and optionally substituted carboxylate, and asaturated or unsaturated ring. These substituents are described above.Where N is included in Y, Y is selected from the moieties set forthhereinabove. In these substituents, “Z” is an aromatic or heteroaromaticmoiety containing 5-12 ring members. Thus, Y may include a single orfused ring. Examples of preferred forms of “Z” are identical to thoseset forth with regard to the aromatic residue “Ar” set forth above, butare monovalent.

[0100] As shown, in certain embodiments, R, defined as H or alkyl(1-6C), is replaced by R⁴ or R⁵ which have a broader definitions and caninclude the embodiments of R as well as embodying optionally substitutedalkenyl, acyl, and the like as set forth above. Preferred forms of R⁴and R⁵ include those typified by R and optionally substituted alkenyl.Also preferred are embodiments where two R⁵ are connected to form acyclic amine, including those which contain one or more additionalheteroatoms such as N, O, and/or S.

[0101] Preferred forms of Y when Y contains N are those wherein R is inall cases H or methyl, preferrably H and those where two R⁵ are coupled.Especially preferred are those of the formula

—(CR₂)_(m)CN,

—(CR₂)_(m)NR⁵ ₂,

—(CR₂)_(m)NR(CR₂)_(m)NRR⁴,

—(CR₂)_(m)CO(CR₂)_(m)NR⁵ ₂,

—(CR₂)_(m)Z,

[0102] and

—NR(CR₂)_(m)Z,

[0103] and those wherein Y comprises guanidino or NHNHR, or amidino;especially wherein (CR₂)_(m) is CH₂, CH₂CH₂, or CH₂CH₂CH₂, or wherein mis 0, and those wherein R⁴ or R⁵ is H or is lower alkyl, alkenyl, orhydrogen, or wherein both R⁵ are identical.

[0104] Particularly preferred are —CH₂NH₂, CH₂CH₂NH₂, CH₂NMe₂,—CH₂CH₂NMe₂, —CONH₂, —CONMe₂, and the like.

[0105] Preferred Z are optionally substituted residues of benzene,oxazole, imidazole, thiazole, benzimidazole, benzthiazole, benzoxazole,indole, thiophene, tetrazine, pyrimidine, pyridine, and the like.

[0106] The novel compounds of Formula 1 of the present invention may beformulated as pharmaceutical compositions that may be administeredtopically; percutaneously, including intravenously; orally; and by otherstandard routes of pharmaceutical administration to mammalian subjectsas determined according to routine clinical practice.

[0107] Having now generally described the invention, the same will bemore readily understood through reference to the following exampleswhich are provided by way of illustration, and are not intended to belimiting of the present invention, unless specified.

Experimental

[0108] The intermediates 8-hydroxy-5,6,7,8-tetrahydroquinoline and8-amino-5,6,7,8-tetrahydroquinoline were prepared according to theprocedures described in Bridger et al. U.S. patent application U.S. Ser.No. 09/535,314, incorporated herein by reference. The intermediateN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanaminewas prepared as described by Bridger et al, U.S. Patent ApplicationsU.S. Ser. No. 60/232,891, and U.S. Ser. No. 60/234,510, incorporatedherein by reference. The intermediate1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole was prepared asdescribed by An, H.; Wang, T.; Mohan, V.; Griffey, R. H.; Cook, P. D.Tetrahedron 1998, 54, 3999-4012.

General Procedures

[0109] General Procedure for N-Alkylation of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-aminewith Mesylates or Alkyl Chlorides

[0110] To a solution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(or amine) (1-1.4 equivalents), N,N,-diisopropylethylamine (or K₂CO₃)(1.5-2 equivalents) and KI (0.05-0.16 equivalent) in CH₃CN(concentration ˜0.1-0.2 M) was added the mesylate or alkyl chloride(such as 1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole) (1-1.4equivalents) and the mixture stirred at 50-70° C. for 3-25 hours, asmonitored by analytical thin layer chromatography. The reaction mixturewas cooled, diluted with CH₂Cl₂ (10 mL/mmol amine) and poured intoeither saturated aqueous NaHCO₃ or brine (10 mL/mmol alcohol). Thephases were separated and the aqueous phase extracted with CH₂Cl₂ (3×10mL/mmol amine). The combined organic phases were dried (Na₂SO₄ or MgSO₄)and concentrated under reduced pressure. The crude material was purifiedby chromatography to afford the desired N-alkylated product.

[0111] General Procedure A: Direct Reductive Amination with NaBH₃CN

[0112] To a stirred solution of the amine (1 equivalent) in anhydrousmethanol (concentration ˜0.1 M), at room temperature, was added thecarbonyl compound (˜1-2 equivalents) in one portion. Once the carbonylhad dissolved (˜5 minutes), NaBH₃CN (˜2-4 equiv.) was added in oneportion and the resultant solution was stirred at room temperature. Thesolvent was removed under reduced pressure and CH₂Cl₂ (20 mL/mmol ofamine) and brine or 1.0 M aqueous NaOH (10 mL/mmol amine) were added tothe residue. The phases were separated and the aqueous phase wasextracted with CH₂Cl₂ (3×10 mL/mmol amine). The combined organic phaseswere dried (Na₂SO₄) and concentrated under reduced pressure. The crudematerial was purified by chromatography.

[0113] General Procedure B: Direct Reductive Amination with NaBH(OAc)₃or NaBH₄

[0114] To a stirred solution of the amine (1 equivalent) in CH₂Cl₂(concentration ˜0.2 M), at room temperature, was added the carbonylcompound (˜1-2 equivalents), glacial acetic acid (0-2 equivalents) andNaBH(OAc)₃ (˜1.5-3 equivalents) and the resultant solution stirred atroom temperature. The reaction mixture was poured into either saturatedaqueous NaHCO₃ or 1.0 M aqueous NaOH (10 mL/mmol amine). The phasesseparated and the aqueous phase extracted with CH₂Cl₂ (3×10 mL/mmolamine). The combined organic phases were dried (Na₂SO₄) and concentratedunder reduced pressure. The crude material was purified bychromatography.

[0115] Similarly, to a stirred solution of the amine (1 equivalent) inanhydrous MeOH (concentration ˜0.1 M), at room temperature, was addedthe carbonyl compound (1 equivalent). The resultant solution was stirredat room temperature or heated to reflux for 4-24 hours. NaBH₄ (1-2equivalents) was added and the resultant mixture stirred at roomtemperature for ˜20 minutes. The reaction mixture was concentrated,dissolved in CH₂Cl₂, washed consecutively with saturated aqueous NaHCO₃and saturated aqueous NaCl. The aqueous layers were extracted withCH₂Cl₂ (2×) and the combined organic extracts were dried (MgSO₄) andconcentrated.

[0116] General Procedure C: Reaction of Alcohols with MethanesulfonylChloride

[0117] To a stirred solution of the alcohol (1 equivalent) and Et₃N(1.5-2 equivalents) in CH₂Cl₂ (or THF) (concentration ˜0.1 M) at roomtemperature (or 0° C.) was added methanesulfonyl chloride (˜1.5equivalents) and the reaction stirred at room temperature for 0.5-1 h.The reaction mixture was poured into either saturated aqueous NaHCO₃ orsaturated NH₄Cl (10 mL/mmol alcohol). The phases were separated and theaqueous phase extracted with CH₂Cl₂ (3×10 mL/mmol amine). The combinedorganic phases were dried (Na₂SO₄) and concentrated under reducedpressure. The crude material was either purified by chromatography orused without further purification in the N-alkylation step.

[0118] General Procedure D: Salt Formation Using Saturated HBr(g) inAcetic Acid

[0119] To a solution of the free base in glacial acetic acid (2 mL) wasadded, a saturated solution of HBr(g) in acetic acid (2 mL). A largevolume of ether (25 mL) was then added to precipitate a solid, which wasallowed to settle to the bottom of the flask and the supernatantsolution was decanted. The solid was washed by decantation with ether(3×25 mL) and the remaining traces of solvent were removed under vacuum.For additional purification, the solid was dissolved in methanol andre-precipitated with a large volume of ether. Washing the solid withether by decantation, followed by drying of the solid in vacuo (0.1Torr) gave the desired compound.

[0120] Intermediates

[0121] Preparation of 4-hydroxymethylbenzaldehyde

[0122] Terephthaldicarboxaldehyde (30.02 g, 224 mmol), methanol (200mL), palladium on activated carbon, (10%, 3.02 g) and2-(aminomethyl)pyridine (2.3 mL, 22 mol, 0.01 mol equiv) were combinedin a hydrogenation vessel and the reaction mixture was shaken on a Parrhydrogenator for 2.5 hours at 40 psi of hydrogen. The mixture wasfiltered through celite, the cake washed with methanol and the solventfrom the eluent removed in vacuo. Purification of the crude product bycolumn chromatography on silica gel (EtOAc/Hexanes, 1:1) afforded thetitle compound (23.8 g, 78%) as a white solid. ¹H NMR (CDCl₃) δ4.80 (s,2H), 7.53 (d, 2H, J=9 Hz), 7.87 (d, 2H, J=9 Hz), 10.00 (s, 1H).

[0123] Preparation of 6,7-Dihydro-5H-quinolin-8-one

[0124] To a stirred solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline(13.96 g, 93.6 mmol) in dry CH₂Cl₂ (400 mL) was added activatedmanganese dioxide (85% purity, 82.22 g, 804 mmol). The resultingheterogeneous mixture was stirred 18 h, at which point the black slurrywas filtered through a cake of celite and washed with CH₂Cl₂ (3×50 mL).The combined washings were concentrated to afford 11.27 g (82%) of thetitle compound as a pale yellow solid, which was used in subsequentreactions without further purification. ¹H NMR (CDCl₃) δ2.17-2.25 (m,2H), 2.82 (t, 2H, J=7 Hz), 3.04 (t, 2H, J=6 Hz), 7.37 (dd, 1H, J=9, 6Hz), 7.66 (dd, 1H, J=9, 1 Hz), 8.71 (dd, 1H, J=6, 1 Hz); ¹³C NMR (CDCl₃)δ22.2, 28.6, 39.2, 126.6, 137.3, 140.5, 147.6, 148.6, 196.5. ES-MS m/z148 (M+H).

[0125] Preparation of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine

[0126] Using General Procedure for N-Alkylation: To a stirred solutionof 8-amino-5,6,7,8-tetrahydroquinoline (7.34 g, 49.6 mmol) in dry CH₃CN(250 mL) was added 1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole(13.22 g, 49.6 mmol), N,N-diisopropylethylamine (15.5 mL, 89.2 mmol) andpotassium iodide (0.41 g, 8.2 mmol) and the mixture was stirred at 60°C. for 3.5 h. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH, 99:1 followed by 97:3 and 96:4) gave the intermediateamine (6.38 g, 34%) as an orange, sticky oil. ¹H NMR (CDCl₃) δ1.76 (s,9H), 1.81-2.10 (m, 2H), 2.25-2.37 (m, 1H), 2.72-2.89 (m, 2H), 3.77-3.84(m, 1H), 4.39 (d, 1H, J=15.0 Hz), 4.56 (d, 1H, J=15.0 Hz), 7.00-7.06 (m,1H), 7.27-7.37 (m, 1H), 7.64-7.74 (m, 1H), 7.90-7.96 (d, 2H, J=8.1 Hz),8.34 (d, 1H, J=3.0 Hz); ¹³C NMR (CDCl₃) δ20.13, 28.48, 29.00, 29.20,47.15, 56.89, 86.20, 115.32, 120.28, 122.06, 124.43, 124.85, 132.77,133.74, 137.01, 142.44, 147.10, 149.22, 154.90, 157.72; ES-MS m/z 279(M+H-boc).

[0127] Preparation of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0128] To a stirred solution of (2-aminomethyl)benzimidazoledihydrochloride hydrate (5.96 g, 27.1 mmol) in dry MeOH (225 mL) wasadded 6,7-dihydro-5H-quinolin-8-one (3.99 g, 27.1 mmol) and the mixturestirred at room temperature for 69 h. To the resultant solution wasadded sodium borohydride (2.06 g, 54.2 mmol) in two portions and themixture stirred for 1.5 h. The reaction mixture was concentrated invacuo and diluted with CH₂Cl₂ (150 mL). The organic layer was washedwith saturated aqueous sodium bicarbonate (200 mL), the aqueous layerextracted with CH₂Cl₂ (2×50 mL) and the combined organic layers dried(Na₂SO₄), filtered, and concentrated in vacuo. Purification by columnchromatography on silica gel (CH₂Cl₂/MeOH, 99:1 followed by 98:2 and96:4) gave the intermediate amine (3.59 g, 50%) as a yellow foam. ¹H NMR(CDCl₃) δ1.66-1.90 (m, 3H), 1.91-2.00 (m, 1H), 2.00-2.17 (m, 1H),2.33-2.69 (br m, 1H), 3.88-3.96 (m, 1H), 4.37 (d, 1H, J=3.0 Hz),7.18-7.26 (m, 4H), 7.48 (d, 1H, J=6.0 Hz), 7.58-7.78 (br m, 1H),8.55-8.58 (m, 1H); ¹³C NMR (CDCl₃) δ19.66, 29.12, 30.24, 46.62, 57.28,122.21, 122.83, 133.55, 138.07, 146.98, 156.17, 157.73.

EXAMPLE 1

[0129]

AMD9679: Preparation ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine

[0130] To a stirred solution of 8-amino-5,6,7,8-tetrahydroquinoline(6.43 g, 43 mmol) in CH₂Cl₂ (450 mL) at room temperature was added3-cyanobenzaldehyde (5.69 g, 43 mmol) and sodium triacetoxyborohydride(17.0 g, 80 mmol) and the mixture stirred 16 h. The reaction wasquenched with 1N NaOH (200 mL) and the phases separated. The organicphase was dried (Na₂SO₄) and concentrated under reduced pressure to givea yellow oil (11.7 g) which was purified by flash chromatography onsilica gel (97:3 CH₂Cl₂/CH₃OH) to provideN-(5,6,7,8-tetrahydro-8-quinolinyl)-3-cyanobenzylamine (9.10 g, 81%) asa pale yellow solid.

[0131] Using the General Procedure for N-Alkylation: A solution of thematerial from above (4.17 g, 15.8 mmol), potassium iodide (130 mg, 0.80mmol) and N,N-diisopropylethylamine (5.2 mL, 30 mmol) in CH₃CN (160 mL)was reacted with N-(tert-butoxycarbonyl)-2-chloromethylbenzimidazole(prepared as described by An, H.; Wang, T.; Mohan, V.; Griffey, R. H.;Cook, P. D Tetrahedron 1998, 54, 3999-4012) (4.22 g, 15.8 mmol).Purification of the crude material by flash chromatography on silica gel(1:1 EtOAc/hexanes) gave the alkylated product (6.86 g, 88%) as a yellowfoam.

[0132] To a solution of the material from above (6.86 g, 13.9 mmol) inNH₃ saturated methanol (100 mL) in a Parr bottle was added Raney nickel(approx 1 g) and the mixture hydrogenated at 50 psi hydrogen in a Parrhydrogenator for 17 h. The product mixture was filtered through Celite521 and the solvent from the eluent removed in vacuo. Purification ofthe crude material by flash chromatographed on silica gel (5%CH₂Cl₂/CH₃OH/NH₄OH, 19:1:0 followed by 18:1:1) gave AMD9679 (4.36 g,79%) as a yellow foamy solid. ¹H NMR (CDCl₃) δ1.58-1.75 (m, 1H),1.96-2.09 (m, 2H), 2.24-2.30 (m, 1H), 2.70-2.94 (m, 2H), 3.74 (s, 2H),3.78 (s, 2H), 3.94-4.20 (m, 3H), 7.07 (d, 1H, J=7.5 Hz), 7.15-7.21 (m,4H), 7.30 (d, 1H, J=7.5 Hz), 7.36 (s, 1H), 7.43 (d, 1H, J=7.5 Hz), 7.47(s, br, 2H), 8.67 (d, 1H, J=4.2 Hz). ¹³C NMR (CDCl₃) δ21.77, 23.70,29.65, 46.47, 49.12, 54.51, 60.78, 121.93(2), 122.65, 126.45, 127.61,127.98, 128.83, 135.23, 137.70, 140.08, 142.72, 147.27, 156.35, 157.72.ES-MS m/z 398 (M+H). Anal. Calcd. for C₂₅H₂₇N₅.1.0H₂O.0.23CH₂Cl₂: C,69.65; H, 6.82; N, 16.10. Found: C, 69.57; H, 6.91; N, 16.30.

EXAMPLE: 2

[0133]

AMD9720: Preparation of(1H-Benzimidazol-2-ylmethyl)-(2-Aminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0134] Preparation of[1-(tert-butoxycarbonyl)-(1H-Benzimidazol-2-ylmethyl)]-(2-cyano-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine:

[0135] Following General Procedure B: To a solution of[1(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(197 mg, 0.523 mmol) and 2-cyanobenzaldehyde (91.2 mg, 0.695 mmol) inCH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (240 mg, 1.13 mmol) and the mixturestirred overnight. Purification of the resultant oil by flashchromatography (15 g silica, 50:1:1 CH₂Cl₂/CH₃OHONH4OH) gave the desiredintermediate (167 mg, 65%). ¹H NMR (CDCl₃) δ1.72 (s, 9H), 1.91-2.15 (m,2H), 2.31-2.42 (m, 1H), 2.62-2.86 (m, 2H), 4.12 (d, 1H, J=15.6 Hz), 4.29(d, 1H, J=15.8 Hz), 4.38 (dd, 1H, J=9.6, 6.1 Hz), 4.64 (s, 2H), 6.93 (t,1H, J=7.6 Hz), 7.00 (dd, 1H, J=7.5, 4.7 Hz), 7.14-7.32 (m, 5H),7.58-7.69 (m, 31H), 8.44 (d, 1H, J=4.6 Hz).

[0136] To a solution of the material from above (101 mg, 0.204 mmol) inNH₃ saturated CH₃OH (4 mL) in a Parr bottle was added Raney nickel (200mg) and the mixture hydrogenated at 50 psi hydrogen in a Parrhydrogenator for 16 h. The product mixture was filtered through celiteand the solvent from the eluent removed in vacuo. Purification of thecrude material by flash chromatography (12 g silica, 50:1:1CH₂Cl₂/CH₃OH/NH₄OH) afforded the deprotected freebase (30 mg, 37%).

[0137] Following General Procedure D: Conversion of the amine from above(30 mg) to the hydrobromide salt gave AMD9720 (39 mg, 77%). ¹H NMR (D₂O)δ1.80-1.97 (m, 1H), 2.17-2.37 (m, 2H), 2.42-2.54 (m, 1H), 2.99-3.08 (m,2H), 3.91 (d, 1H, J=13.0 Hz), 4.16 (d, 2H, J=13.7 Hz), 4.32-4.41 (m,2H), 4.54 (d, 1H, J=16.4 Hz), 6.89-7.00 (m, 2H), 7.15 (t, 1H, J=7.2 Hz),7.41 (d, 1H, J=7.5 Hz), 7.48-7.61 (m, 4H), 7.88 (dd, 1H, J=7.7, 5.9 Hz),8.36 (d, 1H, J=8.0 Hz), 8.71 (d, 1H, J=5.7 Hz). ¹³C NMR (D₂O) δ20.46,20.90, 27.92, 40.14, 48.91, 53.45, 62.31, 113.93 (2 carbons), 126.12,126.79 (2 carbons), 129.35, 129.84, 129.98, 130.67, 131.52, 131.94,135.10, 140.10, 141.02, 148.08 (2 carbons), 150.57, 150.88. ES-MS m/z398 (M+H) Anal Calc. for C₂₅H₂₇N₅.3.0OHBr.1.9H₂O: C, 44.52; H, 5.05; N,10.38; Br, 35.54. Found: C, 44.42; H, 4.97; N, 10.15; Br, 35.86.

EXAMPLE: 3

[0138]

AMD11090: Preparation of(2-Aminomethyl-benzyl)-(1H-benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-amine(hydrochloride salt).

[0139] Preparation of 2-(phthalamido-methyl)-benzaldehyde

[0140] To a stirred, cooled (0° C.) solution of 2-cyanobenzaldehyde(10.4 g, 79.0 mmol) in anhydrous THF (320 mL) was added LAH (14.3 g, 377mmol) portionwise. The slurry was stirred under N₂ at room temperaturefor 15 h. The reaction was slowly quenched with distilled water (15 mL),then 15% (w/v) NaOH (15 mL) followed by more distilled water (45 mL).The mixture was stirred for 20 min, diluted with diethyl ether (200 mL)and the white fluffy precipitate was removed by filtration. The filtratewas dried (MgSO₄) and concentrated in vacuo. The resultant amino alcohol(12.6 g) was used without further purification in the next reaction.

[0141] A solution of the alcohol from above (assumed 79 mmol) andphthalic anhydride (12.3 g, 83 mmol) in 20% MeOH/CHCl₃ (200 mL) wasstirred at reflux for 19 h. The mixture was cooled to room temperatureand purified by flash chromatography (8 cm id., 300 g silica gel, elutedwith 1% MeOH/CH₂Cl₂) followed by recrystallization from hotdichloromethane to give the desired alcohol as a pale pink solid (7.11g, 34% over two steps).

[0142] To a stirred slurry of TPAP (465 mg, 1.3 mmol), NMO (4.7 g, 40mmol) and 3 Å molecular seives (14 g) in CH₂Cl₂ (220 mL) was addeddropwise a solution of the alcohol from above (7.11 g, 27 mmol) inCH₂Cl₂ (50 mL) over 30 min. The black slurry was stirred under N₂ for 40min after the addition, concentrated in vacuo, and purified by flashchromatography (8 cm id., 300 g silica gel, eluted with EtOAc) to affordthe pure title compound as a white solid (5.75 g, 82%). ¹H NMR (CDCl₃)δ5.38 (s, 2H), 7.24-7.28 (m, 1H), 7.44-7.54 (m, 2H), 7.74-7.78 (m, 2H),7.85-7.92 (m, 3H), 10.35 (s, 1H).

[0143] Preparation of(2-Aminomethyl-benzyl)-(1H-benzimidazol-2-ylmethyl)-(S)-5,6,7,8-tetrahydro-quinolin-8-yl-amine(hydrochloride salt) (AMD11090)

[0144] Using General Procedure B: 2-(phthalamido-methyl)-benzaldehydefrom above (5.44 g, 20.5 mmol) was reacted withS-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (3.34 g, 22.6 mmol) andNaBH(OAc)₃ (21.2 g, 100 mmol) in dichloromethane (2.0 L). Flashchromatography (8 cm id, 250 g silica gel, eluted with 5% MeOH/CH₂Cl₂)provided the pure 2° amine as a white foam (6.83 g, 84%).

[0145] To a solution of the amine from above (6.83 g, 17 mmol) inacetonitrile (170 mL) was added diisopropylethylamine (4.5 mL, 26 mmol),1-boc-2-chloromethylbenzimidazole (5.0 g, 19 mmol), and potassium iodide(145 mg, 0.86 mmol). The mixture was stirred under an N₂ atmosphere at60° C. for 15 h, cooled to room temperature and concentrated in vacuo.The residue was partitioned between dichloromethane (200 mL) and brine(100 mL). The separated organic layer was dried (MgSO₄), concentrated,and purified by flash chromatography (8 cm id, 300 g silica gel, elutedwith CH₂Cl₂ to remove unreacted chloride then 2% MeOH/CH₂Cl₂ to removedesired product) to give the pure desired amine (7.6 g, 70%).

[0146] A solution of the amine from above (4.44 g, 7.1 mmol) in ethanol(35 mL) and dichloromethane (2 mL for solubility) was treated withhydrazine monohydrate (2.2 g, 44 mmol) and stirred for 16 h. The mixturewas then concentrated in vacuo and purified by flash chromatography (5cm id., 80 g silica gel, eluted with 3% MeOH/CH₂Cl₂) to give theunprotected amine as a white foamy solid (2.05 g, 73%).

[0147] HCl gas was bubbled through a solution of the amine from above(2.05 g, 5.2 mmol) in glacial acetic acid (20 mL) for 10 min withstirring. The solution was allowed to stir at room temperature 5 min,then it was slowly dropped into diethyl ether (200 mL) with vigorousstirring. The resultant slurry was suction filtered through a glassfritted funnel and the filter cake was washed with diethyl ether (5×50mL) and dried in a vacuum oven at 40° C. for 60 h to give AMD11090 as awhite solid (2.71 g, 96%). ¹H NMR (D₂O) δ1.79-1.97 (m, 1H), 2.17-2.35(m, 2H), 2.44-2.49 (m, 1H), 3.00-3.05 (m, 2H), 3.89 (d, 1H, J=13.5 Hz),4.15 (d, 2H, J=14.1 Hz), 4.30-4.40 (m, 2H), 4.52 (d, 1H, J=16.4 Hz),4.73-4.78 (m, 1H), 6.87-6.98 (m, 2H), 7.12 (td, 1H, J=1.2, 7.5 Hz), 7.38(d, 1H, J=7.5 Hz), 7.47-7.52 (m, 2H), 7.54-7.60 (m, 2H), 7.85-7.90 (m,1H), 8.36 (d, 1H, J=8.1 Hz), 8.71 (d, 1H, J=5.1 Hz); ¹³C NMR (D₂O)δ20.44, 20.86, 27.91, 40.16, 48.88, 53.52, 62.31, 113.91 (2 carbons),126.15, 126.80 (2 carbons), 129.33, 129.78, 129.89, 130.58, 131.54,131.96, 135.01, 140.03, 141.08, 148.19, 150.45, 150.82. ES-MS m/z 398(M+H). Anal. Calcd. for C₂₅H₂₇N₅.3HCl.2H₂O.0.1CH₃COOH: C, 55.14; H,6.32; N, 12.76; Cl, 19.38. Found: C, 55.47; H, 6.50; N, 12.38; Cl,19.26.

[0148] The enantiomeric purity of AMD11090 was determined to be 100% bychiral HPLC using the following conditions: Instrument: Hewlett Packard1100 HPLC (VWD4); Column: ChiralCel OD, 0.46 cm×25 cm; Mobile Phases: A:95:5 hexanes/methanol with 0.1%DEA, B: hexanes; Isocratic: 80% A, 20%B;Total Run Time: 45 min; Flow Rate: 0.5 mL/min; Temperature: 40° C.;Detector: UV @ 270 nm; Injection volume: 10 μL.

[0149] Retention time of the S enantiomer=28.7 min.

[0150] Retention time of the R enantiomer=32.6 min.

EXAMPLE: 4

[0151]

AMD11083: Preparation of(3-aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol

[0152] Preparation of 4-bromomethyl-3-cyano-benzoic acid methyl ester

[0153] 1,2-Dibromoethane (0.016 mL, 0.19 mmol) was added to a suspensionof zinc dust (288 mg, 4.41 mmol) in THF (1 mL), and the mixture washeated to 70° C. for 10 minutes. The mixture was allowed to cool to roomtemperature, TMSCl (0.016 mL, 0.13 mmol) was added, and stirring wascontinued at room temperature for 30 minutes. The mixture was cooled to0° C., a solution of methyl 4-(bromomethyl)benzoate (842 mg, 3.68 mmol)in THF (4 mL) was added over 2 h, and stirring was continued at 0° C.for 2 h. The mixture was cooled to −78° C., a solution of tosyl cyanide(571 mg, 3.15 mmol) in THF (4 mL) was added, and the mixture was stirredat room temperature for 18 h. The mixture was concentrated in vacuo, andthe residue was partitioned between CH₂Cl₂ (20 mL) and saturatedNaHCO₃(aq) (20 mL). The aqueous phase was extracted with CH₂Cl₂ (3×10mL), and the combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. Purification of the crude material by columnchromatography on silica gel (10% EtOAc/hexanes) afforded colourlesscrystals (379 mg). This material was determined by ¹H NMR to be amixture of 3-cyano-4-methyl-benzoic acid methyl ester and anunidentified by-product and was used in the next step without furtherpurification.

[0154] A mixture of the nitrile from above (379 mg), NBS (400 mg, 2.25mmol), and AIBN (53 mg, 0.32 mmol) in CCl₄ (11 mL) was heated at refluxfor 4 days then allowed to cool to room temperature. The mixture wasfiltered, and the filtrate was concentrated in vacuo. Purification ofthe crude material by column chromatography on silica gel (5%EtOAc/hexanes) afforded colourless crystals (100 mg, 12%). ¹H NMR(CDCl₃) δ3.96 (s, 3H), 4.66 (s, 2H), 7.65 (d, 1H, J=8.1 Hz), 8.23 (dd,1H, J=8.1, 1.5 Hz), 8.33 (d, 1H, J=1.5 Hz).

[0155] A mixture of2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (175 mg, 0.462 mmol),4-bromomethyl-3-cyano-benzoic acid methyl ester (98 mg, 0.39 mmol),potassium iodide (4 mg, 0.02 mmol), and N,N-diisopropylethylamine (0.10mL, 0.57 mmol) in acetonitrile (4.0 mL) was heated at 60° C. for 16 h.Saturated NaHCO₃(aq) (15 mL) was added, and the mixture was extractedwith CH₂Cl₂(3×10 mL). The organic extracts were dried (MgSO₄) andconcentrated in vacuo. Purification of the crude material on silica gel(500:5:1 CH₂Cl₂/MeOH/NH₄OH) gave a yellow oil (213 mg, 100%). ¹H NMR(CDCl₃) δ1.73 (m, 10H), 2.01 (m, 2H), 2.38 (m, 1H), 2.76 (m, 2H), 3.86(s, 3H), 4.17 (d, 1H, J=17 Hz), 4.29 (d, 1H, J=17 Hz), 4.37 (m, 1H),4.58 (d, 1H, J=14 Hz), 4.69 (d, 1H, J=14 Hz), 7.01 (dd, 1H, J=7.5, 4.5Hz), 7.18 (m, 2H), 7.31 (d, 1H, J=7.5 Hz), 7.58 (m, 2H), 7.76 (d, 2H,J=1.2 Hz), 7.87 (s, 1H), 8.44 (m, 1H).

[0156] A solution of2-{[(2-cyano-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (213 mg, 0.386 mmol) in saturated NH₃(g)/MeOH (10mL) was shaken at room temperature with a suspension of Raney® nickel(1.5 g) under hydrogen atmosphere (45 psi) for 17 h. The catalyst wasremoved by filtration, and the filtrate was concentrated in vacuo togive a green foam (195 mg).

[0157] To a solution of the crude amine from above (195 mg) in THF (4mL) was added di-t-butyl dicarbonate (220 mg, 1.01 mmol), and thesolution was stirred at room temperature for 3 days. The solution wasconcentrated in vacuo, and the residue was filtered through silica gel(600:5:1 CH₂Cl₂/MeOH/NH₄OH) to give a yellow foam (130 mg).

[0158] To a solution of the crude ester from above (130 mg) in THF (2mL) was added LiAlH₄ (1.0 M/THF, 0.20 mL, 0.20 mmol) at 0° C., and themixture was stirred at 0° C. for 15 minutes. Methanol (1 mL) was addedfollowed by 10% HCl(aq) (1 mL). The mixture was made basic withsaturated NaHCO₃(aq) (30 mL) then extracted with CH₂Cl₂ (4×12 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto give a yellow foam (116 mg).

[0159] A solution of the crude alcohol from above (116 mg) in 3:1TFA/CH₂Cl₂ (4 mL) was stirred at room temperature for 50 minutes thenconcentrated in vacuo. The residue was partitioned between CH₂Cl₂ (10mL) and 1 N NaOH(aq) (15 mL), and the aqueous phase was extracted withCH₂Cl₂ (2×10 mL). The combined organic extracts were dried (MgSO₄) andconcentrated in vacuo. Purification of the crude material by columnchromatography on silica gel (200:5:1-50:5:1 CH₂Cl₂/MeOH/NH₄OH) affordedAMD11083 as a yellow foam (25 mg, 12%). ¹H NMR (CDCl₃) δ1.54 (m, 1H),1.93 (m, 2H), 2.19 (m, 1H), 2.57-2.80 (m, 2H), 3.52-3.88 (m, 7H), 4.54(s, 2H), 6.93 (m, 1H), 7.04 (d, 1H, J=7.5 Hz), 7.15 (m, 4H), 7.25 (m,1H), 7.54 (m, 2H), 8.39 (d, 1H, J=3.6 Hz); ^(—)C NMR (CDCl₃) δ21.77,21.94, 29.47, 43.14, 49.34, 53.99, 59.72, 64.62, 115.42, 122.27, 122.36,126.33, 129.10, 131.52, 135.04, 135.66, 137.51, 141.25, 142.14, 147.24,154.27, 156.94. ES-MS m/z 428 (M+H). Anal. Calcd. forC₂₆H₂₉N₅O.0.2H₂O.1.2CH₂Cl₂: C, 61.29; H, 6.01; N, 13.14. Found: C,61.36; H, 6.02; N, 12.84.

EXAMPLE: 5

[0160]

AMD11120: Preparation of(2-Aminomethyl-3-methoxy-benzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromidesalt)

[0161] To a solution of ethyl 2-methoxy-6-methylbenzoate (1.23 g, 6.33mmol) in dry diethyl ether (58 mL) was added LiAlH₄ (0.467 g, 12.31mmol) and the resultant mixture was heated to reflux for 2 hours thencooled to room temperature. The mixture was treated sequentially withwater (0.45 mL), 15% aqueous NaOH (0.45 mL) and water (1.35 mL). Themixture was filtered through Celite© and the cake was washed with ether(200 mL). The filtrate was concentrated under reduced pressure andprovided 0.96 g (99%) of 2-methoxy-6-methylbenzyl alcohol as a yellowsolid. ¹H NMR (CDCl₃) δ2.27 (t, 1H, J=6.3 Hz), 2.39 (s, 3H), 3.86 (s,3H), 4.75 (d, 2H, J=6.3 Hz), 6.76 (d, 1H, J=8.4 Hz), 6.81 (d, 1H, J=7.8Hz), 7.17 (dd, 1H, J=7.8, 8.4 Hz).

[0162] To a solution of 2-methoxy-6-methylbenzyl alcohol (0.96 g, 6.32mmol) in CH₂Cl₂ (35 mL) was added triethylamine (2.00 mL, 14.35 mmol)followed by methanesulfonyl chloride (0.90 mL, 11.63 mmol) and theresultant solution was heated at 40° C. for 45 minutes then cooled toroom temperature. The mixture was diluted with CH₂Cl₂ (35 mL), washedwith brine (3×15 mL), dried (Na₂SO₄), and concentrated to provide a paleyellow solid. The solid (1.12 g) was dissolved in DMF (35 mL), treatedwith potassium phthalimide (2.62 g, 14.15 mmol), and heated at 80° C.overnight. The mixture was cooled to room temperature and diluted withEtOAc (70 mL), brine (35 mL), and water (20 mL). The phases wereseparated and the organic phase was washed with 1.0 N NaOH (6×10 mL) andbrine (2×20 mL). The organic phase was dried (MgSO₄) and concentrated toprovide an pale yellow solid. The solid was rinsed with hexanes (3×10mL) and provided 1.18 g (66%) of (2-methoxy-6-methylbenzyl)phthalimideas a white solid. ¹H NMR (CDCl₃) δ2.53 (s, 3H), 3.75 (s, 3H), 4.89 (s,2H), 6.70 (d, 1H, J=8.4 Hz), 6.80 (d, 1H), J=7.5 Hz), 7.15 (dd, 1H,J=7.5, 8.4 Hz), 7.66-7.68 (m, 2H), 7.76-7.80 (m, 2H); ^(—)C NMR (CDCl₃)δ20.27, 34.95, 55.90, 108.61, 122.38, 123.17, 123.41, 128.97, 132.60,134.07, 139.55, 158.70, 168.36.

[0163] To a solution of (2-methoxy-6-methylbenzyl)phthalimide (0.286 g,1.02 mmol) in CCl₄ (25 mL) was added recrystallized N-bromosuccinimide(0.177 g, 0.99 mmol) followed by benzoyl peroxide (28 mg, 0.11 mmol).The resultant mixture was heated to reflux for 90 minutes then cooled toroom temperature. The mixture was diluted with diethyl ether (25 mL),filtered through filter paper, and the filtrate was concentrated.Purification of the crude material by column chromatography (3:1hexanes-EtOAc) provided 0.31 g (86%) of(6-(bromomethyl)-2-methoxybenzyl)phthalimide as a white solid. ¹H NMR(CDCl₃) δ3.78 (s, 3H), 4.90 (s, 2H), 5.00 (s, 2H), 6.83 (d, 1H, J=8.4Hz), 6.98 (d, 1H, J=7.2 Hz), 7.25 (dd, 1H, J=7.2, 8.4 Hz), 7.67-7.69 (m,2H), 7.78-7.81 (m, 2H). ES-MS m/z 382 (M+Na), 384 (M+Na).

[0164] To a solution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.202 g, 0.53 mmol) in CH₃CN (5 mL) was added NAN-diisopropylethylamine(0.20 mL, 1.15 mmol) followed by a suspension of(6-(bromomethyl)-2-methoxybenzyl)phthalimide (0.30 g, 0.83 mmol) inCH₃CN (5 mL). The resultant mixture was heated to 60° C. for 18 hoursthen cooled to room temperature. The mixture was concentrated and theresidue was partitioned between CH₂Cl₂ (40 mL) and brine (10 mL). Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(3×10 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification of the crude material by columnchromatography on silica gel (50:1 CH₂Cl₂-CH₃OH) provided 0.212 g (60%)of a white solid.

[0165] The solid (0.21 g) from above was dissolved in ethanol (6 mL),treated with hydrazine monohydrate (0.31 mL, 6.4 mmol), and stirred atroom temperature overnight. The mixture was concentrated and CH₂Cl₂ (50mL) was added to the residue. The resultant suspension was filteredthrough Celite© and the cake was washed with CH₂Cl₂ (50 mL). Thefiltrate was concentrated under reduced pressure and the residue waspartitioned between CH₂Cl₂ (40 mL) and 1.0 N NaOH (10 mL). The phaseswere separated and the aqueous phase was extracted with CH₂Cl₂ (3×10mL). The combined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by radial chromatography on silicagel (1 mm plate, 50:1:1 CH₂Cl₂-CH₃OH-NH₄OH) provided 30 mg (22%) of thefree base of the title compound as a white solid.

[0166] Using General Procedure D: Conversion of the solid from above (30mg, 0.071 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD11120 (34 mg, 67%) asa white solid. ¹H NMR (D₂O) 67 1.91-1.99 (m, 1H), 2.20-2.38 (m, 2H),2.46-2.50 (m, 1H), 3.05-3.13 (m, 2H), 3.38 (s, 3H), 3.90 (d, 1H, J=12.9Hz), 4.11 (d, 1H, J=12.9 Hz), 4.16 (d, 1H, J=12.9 Hz), 4.29 (d, 1H,J=12.9 Hz), 4.34 (d, 1H, J=16.5 Hz), 4.54 (d, 1H, J=16.5 Hz), 4.74-4.79(m, 1H, overlaps with HOD), 6.50 (d, 1H, J=8.4 Hz), 7.01 (d, 1H, J=7.8Hz), 7.21 (dd, 1H, J=7.8, 8.4 Hz), 7.52-7.61 (m, 4H), 7.94 (dd, 1H,J=6.0, 7.8 Hz), 8.42 (d, 1H, J=7.8 Hz), 8.77 (d, 1H, J=6.0 Hz); ¹³C NMR(D₂O) δ20.44, 20.98, 27.93, 35.25, 48.97, 53.77, 55.72, 62.69, 111.43,113.85, 119.53, 124.35, 126.25, 126.89, 130.42, 131.20, 136.39, 139.95,141.28, 148.39, 150.35, 151.05, 157.88. ES-MS m/z 428 (M+H). Anal.Calcd. for C₂₆H₂₂N₅O.3.0HBr.2.8H₂O: C, 43.33; H, 5.26; N, 9.72; Br,33.26. Found: C, 43.47; H, 5.14; N, 9.61; Br, 33.00.

EXAMPLE: 6

[0167]

AMD9903: Preparation of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[(1-aminomethyl)-benzoxazol-3-ylmethyl)]-amine(hydrobromide salt)

[0168] Preparation of1-[N-(t-butoxycarbonyl)-aminomethyl]-3-hydroxymethyloxazole

[0169] Using the procedure of P. Wipf et al. (A. J. Phillips, Y. Uto, P.Wipf, M. J. Reno and D. R. Williams Org. Lett. 2000, 2(8), 1165-1168), a−20° C. solution of N-(t-butoxycarbonyl)-Gly-Ser-OMe (170 mg, 0.615mmol) in dichloromethane (5 mL) was treated withbis(2-methoxyethyl)aminosulfur trifluoride (0.125 mL, 0.677 mmol). Theresulting solution was then stirred at −20° C. for 30 minutes, andbromotrichloromethane (0.212 mL, 2.21 mmol) was added, followed by DBU(0.330 mL, 2.21 mmol). The reaction was allowed to warm to 0° C., andwas stirred at that temperature for 5 hours, then aqueous ammoniumchloride (5 mL) was added. After separation of the aqueous and organiclayers, the aqueous layer was extracted twice with dichloromethane. Thecombined organic fractions were then dried over anhydrous sodium sulfateand concentrated. Purification by chromatography on silica gel (2%methanol in dichloromethane), gavemethyl-1-[N-(t-butoxycarbonyl)-aminomethyl]-oxazole-3-carboxylate as anoil (123 mg, 78%). ¹H NMR (CDCl₃) δ1.25 (s, 9H), 3.88 (s, 3H), 4.51 (d,2H, J=5.8 Hz), 5.22 (br s, 1H), 8.19 (s, 1H).

[0170] The ester (178 mg, 0.695 mmol) in 0° C. dichloromethane (8 mL)was treated with DIBAL-H (1 M in dichloromethane, 2.08 mL, 2.08 mmol).The mixture was then stirred at 0° C. for 2 hours before being treatedwith aqueous 5% sodium potassium tartrate (8 mL). The mixture wasstirred rapidly for 30 minutes (until the aqueous and organic layersclarified), and the layers were then separated. The aqueous layer wasextracted twice with dichloromethane. The combined organic fractionswere then dried over anhydrous sodium sulfate and concentrated.Purification by chromatography on silica gel (5% methanol indichloromethane) gave1-[N-(t-butoxycarbonyl)-aminomethyl]-3-hydroxymethyloxazole as an oil(45 mg, 28%). ¹H NMR (CDCl₃) δ1.40 (s, 9H), 4.43 (d, 2H, J=5.6 Hz), 4.56(s, 2H), 5.37 (s, 1H), 7.54 (s, 1H).

[0171] To a stirred solution of1-[N-(t-butoxycarbonyl)-aminomethyl]-3-hydroxymethyloxazole (45 mg,0.197 mmol) in dichloromethane (5 mL) was added triethylamine (0.055 mL,0.4 mmol) followed by methanesulfonyl chloride (0.023 mL, 0.3 mmol). Theresultant solution was stirred at room temperature for 20 minutes,before being treated with an aqueous saturated ammonium chloridesolution (5 mL). The aqueous layer was extracted twice withdichloromethane. The combined organic fractions were then dried overanhydrous sodium sulfate and concentrated to afford the desiredmesylate, which was used directly and immediately in the next reactionwithout further purification. ¹H NMR (CDCl₃) δ1.45 (s, 9H), 3.07 (s,3H), 4.43 (d, 2H, J=5.6 Hz), 5.15 (s, 2H), 7.73 (s, 1H).

[0172] Using General Procedure for N-Alkylation,O-methanesulfonyl-1-[N-(t-butoxycarbonyl)-aminomethyl]-3-hydroxymethyloxazole(0.197 mmol) was stirred in 60° C. acetonitrile (5 mL) for 4 hours withdiisopropylethylamine (0.05 mL, 0.295 mmol) and(1H-N-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(95 mg, 0.25 mmol). The reaction was then cooled and concentrated. Theresidue was taken up in dichloromethane and extracted with aqueousammonium chloride, dried, concentrated and purified by chromatography onsilica gel (20:1 dichloromethane:methanol) to afford[N-(t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-{[1-N-(t-butoxycarbonyl)-aminomethyl]-benzoxazol-3-ylmethyl}-amine(23 mg, 19%). ¹H NMR (CDCl₃) δ1.46 (s, 9H), 1.63 (s, 9H), 1.91 (m, 1H),2.02 (m, 1H), 2.24 (dq, 1H, J=6.8, 2.1 Hz), 2.51 (m, 1H), 2.61-2.78 (m,2H), 4.27 (m, 1H), 4.43 (d, 2H, J=5.8 Hz), 4.49 (s, 2H), 4.73 (d, 1H,J=16.1 Hz), 5.09 (d, 1H, J=16.1 Hz), 5.15 (m, 1H), 6.88 (dd, 1H, J=7.1,5.4 Hz), 7.13 (d, 1H, J=7.1 Hz), 7.24 (m, 2H), 7.61 (s, 1H), 7.61 (m,1H), 7.74 (m, 1H), 8.23 (d, 1H, J=5.4 Hz).

[0173][N-(t-butoxycarbonyl)-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-{[1-N-(t-butoxycarbonyl)-aminomethyl]-benzoxazol-3-ylmethyl}-amine(23 mg 0.039 mmol), was taken up in acetic acid (1 mL), to which asaturated solution of HBr in acetic acid (1 mL) was added. The mixturewas then stirred, precipitated and isolated as per procedure D to yieldAMD9903 as a white crystalline solid (14 mg). ¹H NMR (D₂O). δ1.84 (m,1H), 2.05 (m, 2H), 2.21 (m, 1H), 3.00 (m, 2H), 3.72 (d, 1H, J=14.1 Hz),3.92 (d, 1H, J=14.1 Hz), 3.99 (d, 2H, J=6.0 Hz), 4.39 (d, 1H, J=16.5Hz), 4.58 (d, 1H, J=16.5 Hz), 4.72 (m, 1H), 7.59 (m, 2H), 7.75 (m, 2H),7.84 (s, 1H), 7.86 (m, 1H), 8.33 (d, 1H, J=8.1 Hz), 8.67 (d, 1H, J=5.8Hz). ¹³C NMR (D₂O) δ20.35, 20.57, 27.62, 35.70, 46.40, 48.16, 60.94,114.15 (2C), 125.95, 127.06 (2C), 139.57, 140.46, 148.03, 151.23,154.96. ES-MS m/z 389 (M+H); Anal. Calcd. for (C₂₂H₂₄N₆O×4 HBr×2.6 H₂O):C, 34.82; H, 4.41; N, 11.07; Br 42.11. Found: C, 35.10; H, 4.44; N,10.73; Br, 41.80.

EXAMPLE: 7

[0174]

AMD9986: Preparation of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-[(1-benzyl-2-aminomethyl)-imidazol-5-ylmethyl)]-amine

[0175] Preparation of 2,5-bis-(hydroxymethyl)-N-benzylimidazole

[0176] Using the procedure of S. Zimmerman et al. (S. C. Zimmerman, K.D. Cramer and A. A. Galan J. Org. Chem. 1989, 54, 1256-1264)N-Benzylimidazole (15 g, 95 mmol) was treated with formaldehyde (60 mLof a 37% aqueous solution), to which glacial acetic acid (8 mL) andsodium acetate (10.5 g) were added. The resulting mixture was stirreduntil homogeneous, then was transferred to a thick-walled glass tube,which was sealed and placed in a 140° C. oil bath for 12 hours. The tubewas then cooled, concentrated, made basic with 10N NaOH, and extractedtwice with a 10:1 isopropanol:chloroform mixture. The combined organicfractions were then dried over anhydrous sodium sulfate andconcentrated. Purification by chromatography on silica gel (7% methanolin dichloromethane) gave 2,5-bis-(hydroxymethyl)-N-benzylimidazole as awhite crystalline solid (4.9 g, 24%). ¹H NMR (CDCl₃) δ4.41 (s, 2H), 4.48(s, 2H), 5.36 (s, 2H), 6.77 (s, 1H), 7.00 (m, 2H), 7.28 (m, 3H).

[0177] To a solution of 2,5-bis-(hydroxymethyl)-N-benzylimidazole (436mg, 2.0 mmol) in dichloromethane (10 mL) was added triethylamine (0.35mL, 2.0 mmol) and acetic anhydride (0.19 mL, 2.0 mmol). The mixture wasthen stirred overnight (16 h) at room temperature. The reaction was thenwashed with aqueous ammonium chloride and the layers separated. Theaqueous layer was extracted twice with dichloromethane. The combinedorganic fractions were then dried over anhydrous sodium sulfate andconcentrated. Purification by chromatography on silica gel (5% methanolin dichloromethane) gave the monoacetate,2-acetoxymethyl-5-hydroxymethyl-N-benzylimidazole, as a white powder(300 mg, 58%). ¹H NMR (CDCl₃) δ1.83 (s, 3H), 4.49 (s, 2H), 5.06 (s, 2H),5.33 (s, 2H), 6.97 (m, 2H), 7.28 (m, 3H).

[0178] To a stirred solution of2-acetoxymethyl-5-hydroxymethyl-N-benzylimidazole (130 mg, 0.5 mmol) indichloromethane (5 mL) was added triethylamine (0.104 mL, 0.75 mmol)followed by methanesulfonyl chloride (0.046 mL, 0.6 mmol). The resultantsolution was stirred at room temperature for 20 minutes, before beingtreated with an aqueous saturated ammonium chloride solution (5 mL). Theaqueous layer was extracted twice with dichloromethane. The combinedorganic fractions were then dried over anhydrous sodium sulfate andconcentrated to afford the desired mesylate, which was used directly andimmediately in the next reaction without further purification. ¹H NMR(CDCl₃) δ1.86 (s, 3H), 4.44 (s, 2H), 5.18 (s, 2H), 5.29 (s, 2H), 6.97(m, 2H), 7.33 (m, 3H).

[0179] Using General Procedure for N-Alkylation,O-methanesulfonyl-2-acetoxymethyl-5-hydroxymethyl-N-benzylimidazole (0.5mmol) was stirred in 60° C. acetonitrile (5 mL) for 4 hours withdiisopropylethylamine (0.130 mL, 0.75 mmol) and(1H-N-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(226 mg, 0.6 mmol). The reaction was cooled and concentrated. Theresidue was taken up in dichloromethane and extracted with aqueousammonium chloride, dried, concentrated and purified by chromatography onsilica gel (20:1 dichloromethane:methanol) to afford[N-(t-butoxycarbonyl)-benzimdazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-acetoxymethyl-N-benzylimidazol-5-yl)-methyl]-aminealong with the product resulting from cleavage of the acetate group(mixture, 138 mg).

[0180] The mixture of products from above (138 mg) was treated withpotassium carbonate (100 mg) in methanol (5 mL) and the suspension wasstirred for 8 hours at room temperature. The mixture was then filteredand concentrated, and the residue purified by silica gel flashchromatography using a 20:1 dichloromethane:methanol mixture as aneluent to afford[1H-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-hydroxymethyl-N-benzylimidazol-5-yl)-methyl]-amineas a pale yellow foam (100 mg, 43% for 2 steps). ¹H NMR (CDCl₃) δ1.61(m, 1H), 1.89 (m, 2H), 2.15 (m, 1H), 2.70 (m, 2H), 3.56 (d, 1H, J=15.1Hz), 3.68 (d, 1H, J=15.1 Hz), 4.00 (s, 2H), 4.01 (m, 1H), 4.35 (s, 2H),5.28 (s, 2H), 6.64 (m, 2H), 6.88 (s, 1H), 7.07 (m, 4H), 7.17 (m, 2H),7.34 (d, 1H, J=7.8 Hz), 7.54 (br s, 1H), 8.45 (d, 1H, J=4.8 Hz).

[0181] To a solution of[1H-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-hydroxymethyl-N-benzylimidazol-5-yl)-methyl]-amine(81 mg, 0.17 mmol) in dichloromethane (5 mL) was added triethylamine(0.095 mL, 0.68 mmol) followed by methanesulfonyl chloride (0.040 mL,0.5 mmol). The resultant solution was stirred at room temperature for 20minutes, before being treated with an aqueous saturated ammoniumchloride solution (5 mL). The aqueous layer was extracted twice withdichloromethane. The combined organic fractions were then dried overanhydrous sodium sulfate and concentrated to afford the desiredmesylate, which was used directly and immediately in the next reactionwithout further purification.

[0182] To a solution of the mesylate (0.17 mmol) in DMF (2 mL) anddichloromethane (2 mL) was added sodium azide (33 mg, 0.51 mmol). Themixture was then heated to 50° C. for 2 hours. After cooling, thesolution was washed with 1N NaOH (5 mL), and extracted repeatedly withdichloromethane. The combined organic fractions were then dried overanhydrous sodium sulfate, concentrated, and purified by silica gel flashchromatography using a 20:1 dichloromethane:methanol mixture as aneluent to afford[1H-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-azamethyl-N-benzylimidazol-5-yl)-methyl]-amineas a white foam (34 mg, 40% over 2 steps). ¹H NMR (CDCl₃) δ1.68 (m, 1H),1.95 (m, 2H), 2.44 (m, 1H), 2.88 (m, 2H), 2.64 (d, 1H, J=16.1 Hz), 3.79(s, 2H), 4.09 (m, 1H), 4.11 (d, 1H, J=13.8 Hz), 4.18 (d, 11H, J=13.8Hz), 4.49 (d, 1H, J=12.8 Hz), 5.71 (d, 1H, J=16.1 Hz), 6.70 (m, 2H),6.90 (m, 1H), 6.91 (s, 1H), 7.18 (m, 2H), 7.20 ) m, 1H), 7.32 (m, 3H),7.58 (d, 1H, J=8.1 Hz), 7.81 (m, 1H), 8.09 (d, 1H, J=4.9 Hz).

[0183] To a solution of[1H-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-azamethyl-N-benzylimidazol-5-yl)-methyl]-amine(34 mg, 0.068 mmol) in methanol (10 mL) was added 5% palladium oncalcium carbonate (Lindlar's catalyst, 30 mg). The suspension was thenplaced under 1 atm hydrogen gas pressure, and was stirred for 12 hoursat room temperature. The mixture was then filtered, and the filtrateconcentrated to afford[1H-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-aminomethyl-N-benzylimidazol-5-yl)-methyl]-amine(23 mg, 71%) as a white foam. ¹H NMR (CDCl₃) δ1.68 (m, 1H), 2.02 (m,2H), 2.35 (m, 1H), 2.64 (m, 2H), 3.48 (br s, 2H, NH₂), 3.80 (m, 2H),3.87 (s, 2H), 4.01 (m, 1H), 4.16 (d, 1H, J=15.3 Hz), 4.51 (d, 1H, J=15.3Hz), 5.26 (d, 1H, J=16.1 Hz), 5.73 (d, 1H, J=16.1 Hz), 6.71 (m, 2H),6.94 (m, 2H), 7.16 (m, 2H), 7.22 (m, 2H), 7.24 (s, 1H), 7.32 (m, 2H),7.66 (m, 1H), 7.85 (m, 1H), 8.08 (d, 1H, J=4.8 Hz).

[0184][1H-benzimidazol-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-[(2-aminomethyl-N-benzylimidazol-5-yl)-methyl]-amine(23 mg, 0.048 mmol) was taken up in acetic acid (1 mL), to which asaturated solution of HBr in acetic acid (1 mL) was added. The mixturewas then stirred, precipitated and isolated as per procedure D to yieldAMD9986 as a white crystalline solid (19 mg). ¹H NMR (D₂O). δ1.77 (m,1H), 2.01 (m, 2H), 2.20 (m, 1H), 2.78 (m, 2H), 3.53 (d, 1H, J=14.8 Hz),4.00 (d, 1H, J=14.8 Hz), 4.29 (m, 2H), 4.41 (d, 1H, J=15.3 Hz), 4.53 (d,1H, J=15.3 Hz), 4.58 (m, 1H), 5.30 (m, 2H), 6.76 (m, 2H), 7.19 (m, 4H),7.51 (s, 1H), 7.64 (m, 2H), 7.82 (m, 2H), 8.28 (d, 1H, J=7.8 Hz), 8.63(d, 1H, J=4.9 Hz). ¹³C NMR (D₂O) δ20.01, 20.19, 27.69, 33.06, 33.81,45.27, 48.21, 48.74, 59.46, 114.36, 125.27, 125.72, 125.89, 126.09,127.24, 129.02, 129.71, 130.91, 130.99, 133.72, 138.88, 140.95, 141.29,148.26, 149.94. ES-MS m/z 478 (M+H); Anal. Calcd. for (C₂₂H₂₄N₆O×4HBr×2.5 H₂O×0.7 HOAc): C, 41.10; H, 4.86; N, 11.04; Br Found: C, 41.16;H, 4.82; N, 11.04; Br, 36.06.

EXAMPLE: 8

[0185]

AMD9813: Preparation of 6-aminomethylpyridin-3-ylmethyl-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine

[0186] Preparation of 3-hydroxymethyl-6-cyanopyridine

[0187] To a solution of ethyl-6-cyanonicotinate (prepared as per T.Sakamoto, S. Kaneda, S. Nishimura and H. Yamanaka Chem. Pharm. Bull.1985, 33, 565) (1.58 g, 8.97 mmol) in MeOH (40 mL) was added NaBH₄ (1.00g, 26.4 mmol) and the reaction stirred at room temperature for 8 h.After removal of the solvent, the residue was taken up in 15% NaOH (5mL) and stirred for 20 min. The mixture was then extracted repeatedlywith CH₂Cl₂, and the combined organic fractions were dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification of theresidue by chromatography on silica gel (EtOAc/hexanes, 1:1) afforded3-hydroxymethyl-6-cyanopyridine (414 mg, 34%). ¹H NMR (CDCl₃) δ5.16 (s,2H), 7.69 (d, 1H, J=6.8 Hz), 7.84 (d, 1H, J=6.8 Hz), 8.71 (s, 1H).

[0188] Using General Procedure C: To a solution of3-hydroxymethyl-6-cyanopyridine (30 mg, 0.222 mmol) in CH₂Cl₂ (2 mL) wasadded methanesulfonyl chloride (0.022 mL, 0.289 mmol) and triethylamine(0.046 mL, 0.333 mmol) and the mixture stirred for 60 min at roomtemperature. Purification of the crude product by chromatography onsilica gel (10:1 CH₂Cl₂/eOH) gave the desired mesylate as a pale yellowsolid (22 mg, 47%). ¹H NMR (CDCl₃) δ3.14 (s, 3H), 5.32 (s, 2H), 7.75 (d,1H, J=6.8 Hz), 7.91 (d, 1H, J=6.8 Hz), 8.75 (s, 1H).

[0189] Using the General N-Alkylation Procedure: To a solution of themesylate from above (22 mg, 0.104 mmol), potassium iodide (3 mg, 0.015mmol) and potassium carbonate (22 mg, 0.156 mmol) in CH₃CN (3 mL) wasadded(1-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(60 mg, 0.156 mmol) and the mixture heated to 70° C. for 4 h.Purification of the crude material by chromatography on silica gel (10:1CH₂Cl₂/MeOH) afforded6-cyanopyridin-3-yl-(1H-N-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(32 mg, 63%). ¹H NMR (CDCl₃) δ1.68 (s, 9H), 1.91-2.04 (m, 2H), 2.22 (m,1H), 2.72-2.79 (m, 2H), 3.80 (d, 1H, J=16.1 Hz), 3.98 (d, 1H, J=16.1Hz), 4.31 (dd, 1H, J=12.1, 6.2 Hz), 4.58 (d, 1H, J=16.8 Hz), 4.76 (d,1H, J=16.8 Hz), 7.02 (m, 2H), 27.24-7.31 (m, 3H), 7.61-7.63 (m, 3H),8.44 (d, 1H, J=5.1 Hz), 8.53 (d, 1H, J=4.1 Hz).

[0190] Raney Nickel (65 mg of a 65% slurry in water) was added to asolution of6-cyanopyridin-3-yl-(1H-N-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(32 mg, 0.065 mmol) in MeOH (2 mL) and the solution was saturated withanhydrous ammonia. The mixture was hydrogenated in a Parr bottle at 50psi for 6 h and the mixture filtered through celite, washing the cakewith MeOH. The solvent from the eluent was removed under reducedpressure and the resultant crude material was purified by chromatographyon silica gel (85% CH₂Cl₂, 12% MeOH, 3% NH₄OH) to afford6-aminomethylpyridin-3-yl-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amineas a white foam (18 mg, 70%). ¹H NMR (CDCl₃) δ1.62 (m, 1H), 1.94-2.08(m, 2H), 2.25-2.31 (m, 1H), 2.70-2.92 (m, 2H), 3.49 (s, 2H), 3.72 (s,2H), 3.85 (br s, 2H (NH)), 4.00 (d, 2H, J=16.5 Hz), 4.08 (dd, 1H,.J=12.1, 8.3 Hz), 4.13 (d, 1H, J=16.5 Hz), 7.10-7.22 (m, 4H), 7.43 (d,1H, J=7.2 Hz), 7.53 (m, 2H), 7.69 (d, 1H, J=7.8 Hz), 8.58 (s, 1H), 8.66(d, 1H, J=4.8 Hz).

[0191] Following General Procedure D: Conversion of the amine from above(18 mg, 0.045 mmol) to the hydrobromide salt gave AMD9813 as a whitesolid (28 mg). ¹H NMR (D₂O). δ1.86 (m, 1H), 2.23 (m, 2H), 2.46 (m, 1H),3.04 (m, 2H), 3.69 (d, 1H, J=14.9 Hz), 3.76 (d, 1H, J=14.9 Hz), 3.93 (q,2H, J=13.4 Hz), 4.46 (d, 1H, J=16.8 Hz), 4.67 (d, 1H, J=16.8 Hz), 4.78(m, 1H), 7.06 (d, 1H, J=7.8 Hz), 7.55 (m, 2H), 7.62 (m, 2H), 7.69 (dd,1H, J=8.1, 6.0 Hz), 8.35 (d, 1H, J=1.8 Hz), 8.44 (d, 1H, J=8.1 Hz), 8.77(d, 1H, J=4.5 Hz). ¹³C NMR (D₂O) δ20.38, 20.83, 27.84, 42.67,49.63,53.93, 62.71, 114.05 (2C), 122.99, 126.22, 127.03 (2C), 130.50, 132.87,133.10, 139.87 (2C), 141.14, 148.41, 149.98, 150.49, 151.44, 154.29.ES-MS m/z 399 (M+H); Anal. Calcd. for (C₂₄H₂₆N₆×3.8 HBr×2.2 H₂O):C,38.66; H, 4.62; N, 11.27; Br 40.72. Found: C, 39.98; H, 4.68; N,10.97; Br, 40.63.

EXAMPLE: 9

[0192]

AMD9739: Preparation of[4-(2-amino-ethyl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0193] Preparation of [2-(4-Formyl-phenyl)-ethyl]-carbamic acidtert-butyl ester

[0194] A mixture of methyl 4-(bromomethyl)benzoate (10.09 g, 44.05mmol), sodium cyanide (6.42 g, 131 mmol) and cetyltrimethylammoniumbromide (1.59 g, 4.36 mmol) in benzene/water (2:1, 187.5 mL) was heatedat reflux for 5 h then extracted with CH₂Cl₂ 3×50 mL). The organicextracts were dried (MgSO₄), filtered and concentrated under reducedpressure. Purification of the crude material by chromatography on silicagel (35% EtOAc/hexanes) gave 4-cyanomethyl-benzoic acid methyl ester asa colourless solid (4.64 g, 60%). ¹H NMR (CDCl₃) δ3.82 (s, 2H), 3.93 (s,3H), 7.42 (d, 2H, J=9 Hz), 8.06 (d, 2H, J=9 Hz).

[0195] To a solution of the nitrile from above (1.57 g, 8.96 mmol) inNH₃ saturated CH₃OH (30 mL) in a Parr bottle was added Raney nickel (5g) and the mixture hydrogenated at 45 psi hydrogen in a Parrhydrogenator for 67 h. The product mixture was filtered through celiteand the solvent from the eluent removed in vacuo to give a green liquid(1.30 g). A solution of the green liquid (1.29 g) and di-t-butyldicarbonate (1.90 g, 8.71 mmol) in THF (24 mL) was stirred at roomtemperature for 2 hours then concentrated. Purification of the crudematerial on silica gel (20% EtOAc/hexanes) gave4-(2-tert-Butoxycarbonylamino-ethyl)-benzoic acid methyl ester (1.37 g,55%) as colourless crystals. ¹H NMR (CDCl₃) δ1.43 (s, 9H), 2.86 (m, 2H),3.39 (m, 2H), 3.91 (s, 3H), 4.53 (br s, 1H), 7.26 (d, 2H, J=8.1 Hz),7.98 (d, 2H, J=8.1 Hz).

[0196] To a solution of the ester from above (606 mg, 2.17 mmol) in THF(4 mL) at 0° C. was added diisobutylaluminum hydride (1.0 M/THF, 13 mL,13 mmol). The mixture was stirred at room temperature for 1 hour thenwater was added followed by 10% aqueous HCl until acidic (pH 1-2). Themixture was made basic with 1N NaOH(aq) and extracted with CH₂Cl₂. Theorganic extracts were dried (MgSO₄), filtered and concentrated.Purification of the crude material by chromatography on silica gel (30%EtOAc/hexanes) gave [2-(4-Hydroxymethyl-phenyl)-ethyl]-carbamic acidtert-butyl ester (370 mg, 68%) as colourless crystals. ¹H NMR (CDCl₃)δ1.44 (s, 9H), 2.80 (m, 2H), 3.37 (m, 2H), 4.53 (br s, 1H), 4.68 (d, 2H,J=5.7 Hz), 7.19 (d, 2H, J=7.8 Hz), 7.32 (d, 2H, J=7.8 Hz).

[0197] To a solution of the alcohol from above (200 mg, 0.796 mmol) inCH₂Cl₂ (8 mL) was added activated MnO₂ (814 mg, 7.96 mmol) and themixture stirred at room temperature for 69 h. The reaction mixture wasfiltered through Celite and the cake was washed with CH₂Cl₂. The solventwas removed from the filtrate under reduced pressure to give the desiredaldehyde as colourless crystals (175 mg, 88%). ¹H NMR (CDCl₃) δ1.43 (s,9H), 2.89 (m, 2H), 3.41 (m, 2H), 4.55 (br s, 1H), 7.37 (d, 2H, J=8.1Hz), 7.83 (d, 2H, J=7.8 Hz), 9.99 (s, 1H).

[0198] Using General Procedure B: To a solution of[1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(102 mg, 0.27 mmol) and [2-(4-formyl-phenyl)-ethyl]-carbamic acidtert-butyl ester (81 mg, 0.32 mmol) in THF (3 mL) was added acetic acid(0.017 mL, 0.30 mmol) and NaBH(OAc)₃ (187 mg, 0.882 mmol) and themixture stirred for 46 h. Purification of the crude yellow oil bychromatography on silica gel (300:5:1 CH₂Cl₂/MeOHONH₄OH) gave acolourless foam (153 mg).

[0199] A solution of the colourless foam in 1:1 trifluoroaceticacid/CH₂Cl₂ (4 mL) was stirred at room temperature for 45 min thenconcentrated. The residue was partitioned between CH₂Cl₂ (10 mL) andsaturated aqueous NaHCO₃ (10 mL), and the aqueous phase was extractedwith CH₂Cl₂ (3×10 mL). The combined organic phases were dried (MgSO₄)and concentrated. Purification of the crude material by columnchromatography on silica gel (100:5:1 EtOAc/MeOH/NH₄OH) gave acolourless oil (38 mg, 35%).

[0200] Using General Procedure D: Conversion of the colourless oil fromabove (38 mg, 0.092 mmol) to the hydrobromide salt gave AMD9739 (50 mg,79%) as a colourless solid. ¹H NMR (D₂O) δ1.94 (m, 1H), 2.26 (m, 2H),2.43-2.60 (m, 5H), 3.03 (m, 2H), 3.74 (d, 1H, J=13 Hz), 3.82 (d, 1H,J=13 Hz), 4.42 (d, 1H, J=16 Hz), 4.60 (d, 1H, J=16 Hz), 4.79 (m, 1H),6.85 (d, 2H, J=7.8 Hz), 7.14 (d, 2H, J=7.8 Hz), 7.47-7.59 (m, 4H, 7.91(m, 1H), 8.37 (d, 1H, J=7.8 Hz), 8.75 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O)δ18.88, 19.33, 26.26, 30.88, 38.90, 48.70, 55.03, 61.59, 112.33, 124.34,124.75, 127.27, 128.98, 129.38, 133.59, 135.32, 138.18, 139.18, 146.31,149.49, 150.55. ES-MS m/z 412 (M+H). Anal Calcd for (C₂₆H₂₉N₅) 3.0(HBr)1.8(H₂O): C, 45.48; H, 5.23; N, 10.20; Br, 34.91. Found: C, 45.45; H,5.13; N, 9.95; Br, 34.94.

EXAMPLE: 10

[0201]

AMD9756: Preparation of[4-(3-amino-propyl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0202]

[0203] Preparation of 3-(4-chloromethyl-phenyl)-propionitrile

[0204] Acetonitrile (0.30 mL, 5.7 mmol) was added to a solution ofn-butyllithium (2.4 m in hexanes, 1.96 mL, 4.7 mmol) in dry THF (5 mL)at −78° C. and stirred for 45 min. solution of α,α′-dichloro-p-xylene(2.485 g, 14.2 mmol) in dry THF at −78° C. was added to give a yellow,cloudy solution. The mixture was stirred at −78° C. for an additionalhour and quenched with saturated aqueous NaCl (30 mL) before warming toroom temperature. The mixture was extracted with CH₂Cl₂ (3×200 mL). Thecombined organic extracts were dried over MgSO₄ and concentrated to awhite solid (2.45 g). The product was purified by column chromatographyon silica gel (10:1-EtOAc:Hex) to give the desired nitrile (1.49 g, 60%)as a light yellow syrup. ¹H NMR (300 MHz, CDCl₃) δ7.37 (d, 2H, J=8.1Hz), 7.24 (d, 2H, J=8.1 Hz), 4.58 (s, 2H), 2.96 (t, 2H, J=7.4 Hz), 2.62(t, 2H, J=7.4 Hz).

[0205] Using the general alkylation procedure C: To a stirred solutionof 3-(4-chloromethyl-phenyl)-propionitrile (63 mg, 0.35 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(121 mg, 0.32 mmol) in dry CH₃CN (3 mL) was added KI (2.6 mg, 0.016mmol) and N,N-diisopropylethylamine (0.08 mL, 0.48 mmol) and the mixturewas heated to 60° C. for 24 h. The product was purified by columnchromatography on silica gel (200:1:1-CH₂Cl₂:MeOH:NH₄OH) to give thedesired coupled product (128 mg, 77%) as a yellow syrup. ¹H NMR (300MHz, CDCl₃) δ8.46 (d, 1H, J=3.6 Hz), 7.65-7.61 (m, 1H), 7.55-7.51 (m,1H), 7.28 (d, 1H, J=9.6 Hz), 7.20-7.15 (m, 4H), 7.04-7.00 (m, 1H), 6.77(d, 2H, J=8.1 Hz), 4.74 (d, 1H, J=14.4 Hz), 4.66 (d, 1H, J=14.4 Hz),4.36-4.30 (m, 1H), 3.87 (d, 1H, J=14.7 Hz), 3.73 (d, 1H, J=14.7 Hz),2.77-2.63 (m, 4H), 2.30-2.25 (m, 3H), 2.02-1.94 (m, 2H), 1.74-1.71 (m,10H).

[0206] A solution of2-{[[4-(2-cyano-ethyl)-benzyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (128 mg, 0.24 mmol) in MeOH (10 mL) was saturatedwith NH₃(g). Raney nickel (˜2 g, excess) was rinsed with MeOH (3×),transferred into the hydrogenation flask containing the nitrile and themixture was hydrogenated at 45 psi for 16 h. The product mixture wasdiluted with MeOH (100 mL) and filtered through celite and the solventfrom the eluent removed in vacuo. The product was purified by columnchromatography on silica gel (100:1:1-CH₂Cl₂:MeOH:NH₄OH) to give thedesired amine (51 mg, 50%) as a white foam. ¹H NMR (300 MHz, CDCl₃)δ8.70 (d, 1H, J=3.6 Hz), 7.59 (br s, 2H), 7.42 (d, 1H, J=8.1 Hz), 7.30(d, 2H, J=8.1 Hz), 7.20-7.15 (m, 3H), 7.04 (d, 2H, J=7.8 Hz), 4.17(d,1H, J=16.8 Hz), 4.12-4.06 (m, 1H), 3.97 (d, 1H, J=16.8 Hz), 3.71 (s,2H), 2.86-2.74 (m, 2H), 2.66 (t, 2H, J=6.9 Hz), 2.56 (t, 2H, J=7.8 Hz),2.33-2.24 (m, 1H), 2.09-1.98 (m, 2H), 1.73-1.64 (m, 3H).

[0207] Following General Procedure D: Conversion of the foam from above(51 mg) to the hydrobromide salt gave AMID9756. ¹H NMR (300 MHz, D₂O)δ8.75 (d, 1H, J=5.7 Hz), 8.40 (d, 1H, J=7.8 Hz), 7.93 (dd, 1H, J=7.8,5.7 Hz), 7.60-7.56 (m, 2H), 7.53-7.47 (m, 2H), 7.11 (d, 2H, J=7.8 Hz),6.83 (d, 2H, J=8.1 Hz), 4.78-4.73 (m, 1H), 4.62 (d, 1H, J=16.5 Hz), 4.44(d, 1H, J=16.5 Hz), 3.82 (d, 1H, J=12.3 Hz), 3.75 (d, 1H, J=12.3 Hz),3.06-3.03 (m, 2H), 2.76 (t, 2H, J=7.8 Hz), 2.46-2.43 (m, 1H), 2.34-2.17(m, 4H), 2.97-1.91 (m, 1H), 1.46-1.35 (m, 2H); ¹³C NMR (75.5 MHz, D₂O)δ153.8, 152.7, 150.0, 143.1, 142.7, 141.4, 135.8, 132.3, 132.2, 130.3,128.4, 127.9, 115.7, 65.0, 58.4, 52.1, 41.2, 33.3, 30.4, 29.7, 22.7,22.3. ES-MS m/z 426.3 (M+H). Anal Calcd for(C₂₇H₃₁N₅).2.9(HBr).1.9(H₂O): C, 46.70; H, 5.47; N, 10.08; Br, 33.37.Found: C, 46.69; H, 5.14; N, 10.03; Br, 33.43.

EXAMPLE: 11

[0208]

AMD9768: Preparation ofN-(4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-hydroxylamine

[0209] A solution of4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(350 mg, 0.883 mmol) and hydroxylamine hydrochloride (100 mg, 1.44 mmol)in MeOH (3 mL) was stirred at room temperature for 45 minutes thenconcentrated in vacuo. The residue was partitioned between saturatedNaHCO₃(aq) (15 mL) and CH₂Cl₂ (20 mL), and the aqueous phase wasextracted with CH₂Cl₂ (10 mL). The combined organic phases were dried(MgSO₄), filtered and concentrated in vacuo to give a yellow solid (363mg).

[0210] To a solution of the crude oxime from above (90 mg, 0.22 mmol) in6:1 MeOH/THF (2.2 mL) was added NaBH₄ (19 mg, 0.50 mmol) and thesolution was adjusted to pH 4 using saturated HCl/1,4-dioxane. Themixture was stirred at room temperature for 15 minutes, then additionalNaBH₄ (19 mg, 0.50 mmol) was added and the solution was adjusted to pH4. The mixture was stirred for 15 minutes then made basic using 1 NNaOH(aq) and extracted with CH₂Cl₂ (3×15 mL). The combined extracts weredried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude material by column chromatography on silica gel (100:5:1CH₂Cl₂/MeOH/NH₄OH) afforded AMD9768 (67 mg, 68%) as a colourless foam.¹H NMR (CDCl₃) δ1.66 (m, 1H), 1.99 (m, 2H), 2.24 (m, 1H), 2.67-2.90 (m,2H), 3.71 (s, 2H), 3.94 (d, 1H, J=17 Hz), 3.94 (s, 2H), 4.07 (m, 1H),4.14 (d, 1H, J=17 Hz), 7.17 (m, 5H), 7.38 (m, 3H), 7.55 (m, 2H), 8.66(d, 1H, J=3.9 Hz); ¹³C NMR (CDCl₃) δ21.34, 23.30, 29.18, 48.50, 53.81,57.91, 60.37, 121.87, 122.36, 128.80, 129.06, 134.94, 136.13, 137.55,138.46, 146.72, 155.89, 157.15. ES-MS m/z 414 (M+H). Anal. Calcd. forC₂₅H₂₇N₅O.0.3H₂O.0.36CH₂Cl₂: C, 67.76; H, 6.35; N, 15.58. Found: C,67.85; H, 6.39; N, 15.51.

EXAMPLE: 12

[0211]

AMD11088: Preparation of(5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol

[0212] Preparation of 2-methyl-5-nitro-benzoic acid methyl ester

[0213] A solution of 2-methyl-5-nitrobenzoic acid (1.51 g, 8.34 mmol)and H₂SO₄ (catalytic) in MeOH (20 mL) was heated at reflux for 17 h,then concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (40 mL),washed with saturated NaHCO₃(aq) (30 mL), then dried (MgSO₄) andconcentrated in vacuo to give yellow crystals (1.62 g, 99%). ¹H NMR(CDCl₃) δ2.72 (s, 3H), 3.96 (s, 3H), 7.44 (d, 1H, J=8.7 Hz), 8.24 (dd,1H, J=8.7, 2.7 Hz), 8.78 (d, 1H, J=2.7 Hz).

[0214] Preparation of 5-Amino-2-methyl-benzoic acid methyl ester

[0215] A solution of 2-methyl-5-nitro-benzoic acid methyl ester (1.96 g,10.0 mmol) in 4:1 MeOH/EtOAc (25 mL) was shaken at room temperature witha suspension of 10% Pd/C (200 mg, 0.19 mmol) under hydrogen atmosphere(35 psi) for 2 h. The catalyst was removed by filtration, and thefiltrate was concentrated in vacuo to give an orange oil (1.64 g, 99%).¹H NMR (CDCl₃) δ2.47 (s, 3H), 3.62 (br s, 2H), 3.87 (s, 3H), 6.75 (dd,1H, J=8.1, 2.7 Hz), 7.02 (d, 1H, J=8.1 Hz), 7.25 (d, 1H, J=2.7 Hz).

[0216] Preparation of 5-Cyano-2-methyl-benzoic acid methyl ester

[0217] To a stirred suspension of 5-amino-2-methyl-benzoic acid methylester (1.00 g, 6.05 mmol) in H₂O (1.5 mL) was slowly added conc. HCl(1.5 mL) at room temperature. More H₂O (7 mL) was added, and the mixturewas stirred at 0° C while a solution of NaNO₂ (459 mg, 6.65 mmol) in H₂O(1 mL) was added dropwise. After the amine had completely dissolved,K₂CO₃(s) was added slowly at 0° C. until the solution was neutralized.

[0218] Copper(I) cyanide (651 mg, 7.27 mmol) was dissolved in a solutionof NaCN (712 mg, 14.5 mmol) in H₂O (2.2 mL), and the solution was heatedto 60° C. The cold neutralized diazonium salt solution was addeddropwise to the vigorously stirred cyanide solution at 60° C. Themixture was heated to 110° C. for 30 minutes then allowed to cool toroom temperature. The mixture was diluted with saturated NaHCO₃(aq) (10mL) and extracted with CH₂Cl₂ (4×12 mL). The combined organic extractswere dried (MgSO₄) and concentrated in vacuo. The crude material wasfiltered through silica gel (10% EtOAc/hexanes) to give yellow crystals(896 mg, 85%). ¹H NMR (CDCl₃) δ2.68 (s, 3H), 3.93 (s, 3H), 7.37 (d, 1H,J=8.1 Hz), 7.66 (dd, 1H, J=7.8, 1.8 Hz), 8.22 (d, 1H, J=1.8 Hz).

[0219] Preparation of 2-Bromomethyl-5-cyano-benzoic acid methyl ester

[0220] A mixture of 5-cyano-2-methyl-benzoic acid methyl ester (894 mg,5.10 mmol), NBS (1.00 g, 5.62 mmol), and AIBN (125 mg, 0.761 mmol) inCCl₄ (20 mL) was heated at reflux for 3 days then allowed to cool toroom temperature. The mixture was filtered, and the filtrate wasconcentrated in vacuo. Purification of the crude material by columnchromatography on silica gel (5% EtOAc/hexanes) afforded yellow crystals(800 mg, 62%). ¹H NMR (CDCl₃) δ3.99 (s, 3H), 4.96 (s, 2H), 7.61 (d, 1H,J=8.1 Hz), 7.77 (dd, 1H, J=8.1, 1.8 Hz), 8.27 (d, 1H, J=1.8 Hz).

[0221] A mixture of2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (253 mg, 0.668 mmol),2-bromomethyl-5-cyano-benzoic acid methyl ester (170 mg, 0.669 mmol),potassium iodide (6 mg, 0.04 mmol), and N,N-diisopropylethylamine (0.17mL, 0.98 mmol) in acetonitrile (6.7 mL) was heated at 60° C. for 18 h.Saturated NaHCO₃(aq) (15 mL) was added, and the mixture was extractedwith CH₂Cl₂ (3×15 mL). The organic extracts were dried (MgSO₄) andconcentrated in vacuo. Purification of the crude material on silica gel(500:5:1 CH₂Cl₂/MeOH/NH₄OH) gave a yellow foam (360 mg, 98%). 1H NMR(CDCl₃) δ1.74 (m, 10H), 1.99 (m, 2H), 2.29 (m, 1H), 2.74 (m, 2H), 3.86(s, 3H), 4.22 (d, 1H, J=17 Hz), 4.33 (m, 1H), 4.36 (d, 1H, J=17 Hz),4.59 (d, 1H, J=14 Hz), 4.65 (d, 1H, J=14 Hz), 6.98 (dd, 1H, J=8.0, 4.7Hz), 7.25 (m, 3H), 7.33 (dd, 1H, J=8.1, 1.8 Hz), 7.50 (m, 1H), 7.68 (m,2H), 8.11 (d, 1H, J=8.1 Hz), 8.41 (m, 1H).

[0222] A solution of2-{[(4-cyano-2-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (356 mg, 0.645 mmol) in saturated NH₃(g)/MeOH (20mL) was shaken at room temperature with a suspension of Raney® nickel(1.5 g) under hydrogen atmosphere (45 psi) for 20 h. The catalyst wasremoved by filtration, and the filtrate was concentrated in vacuo. Thecrude material was filtered through silica gel (100:5:1CH₂Cl₂/MeOH/NH₄OH) to give a yellow oil (203 mg, 69%). ¹H NMR (CDCl₃)δ1.69 (m, 1H), 2.01 (m, 2H), 2.27 (m, 1H), 2.80 (m, 2H), 3.69 (br s,2H), 3.90 (m, 5H), 4.10 (d, 1H, J=17 Hz), 4.15 (m, 1H), 4.53 (d, 1H,J=14 Hz), 7.19 (m, 4H), 7.41 (m, 1H), 7.47 (m, 1H), 7.58 (m, 2H), 7.68(d, 1H, J=7.8 Hz), 8.62 (m, 1H).

[0223] To a solution of5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid methyl ester (192 mg, 0.421 mmol) in THF (4.2 mL) was added LiAlH₄(1.0 M/THF, 0.42 mL, 0.42 mmol) at 0° C., and the mixture was stirred at0° C. for 15 minutes. To the mixture was added H₂O (0.016 mL) followedby 15% NaOH(aq) (0.016 mL) and H₂O (0.048 mL). The mixture was allowedto warm to room temperature then filtered and concentrated in vacuo.Purification of the crude material by column chromatography on silicagel (100:5:1 CH₂Cl₂/MeOH/NH₄OH) afforded AMD1088 as a colourless foam(29 mg, 15%). 1H NMR (CDCl₃) δ1.69 (m, 1H), 2.04 (m, 2H), 2.36 (m, 1H),2.80 (m, 2H), 3.69 (s, 2H), 3.78-4.07 (m, 5H), 4.52 (d, 1H, J=12 Hz),4.62 (d, 1H, J=12 Hz), 6.97 (dd, 1H, J=7.5, 1.5 Hz), 7.13 (m, 4H, 7.29(d, 1H, J=1.5 Hz), 7.44 (m, 3H), 8.46 (m, 1H); ¹³C NMR (CDCl₃) δ21.09,21.41, 29.05, 45.95, 49.53, 55.39, 61.07, 62.90, 121.81, 122.28, 126.35,130.44, 131.20, 134.88, 135.67, 137.72, 140.42, 143.53, 146.80, 153.73,156.25. ES-MS m/z 428 (M+H). Anal. Calcd. forC₂₆H₂₉N₅O.0.4H₂O.0.3CH₂Cl₂: C, 68.64; H, 6.66; N, 15.22. Found: C,68.67; H, 6.67; N, 15.25.

EXAMPLE: 13

[0224]

AMD1071: Preparation of2-Aminomethyl-5-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenol(hydrobromide salt)

[0225] 2-Hydroxy-4-methylbenzonitrile was prepared following amodification of the procedure reported by Makoto Adachi and TsutomuSugasawa (Synthetic Communications 1990, 20, 71-84.). To a cold (0° C.)solution of BCl₃ (1.0 M in heptane, 12.0 mL, 12.0 mmol) in1,2-dichloroethane was added neat m-cresol (1.00 mL, 9.56 mmol) followedby CH₃SCN (0.83 mL, 12.1 mmol) and AlCl₃ (1.38 g, 10.4 mmol). Thecooling bath was removed and the resultant mixture was heated to 80° C.for 3 hours then cooled to room temperature. The mixture was poured into4 N NaOH (35 mL) and the mixture was heated at 80° C. for 45 minutesthen cooled to room temperature. The phases were separated and theaqueous phase was extracted with CH₂Cl₂ (3×50 mL). The aqueous phase wasacidified with 6 N HCl (30 mL) and extracted with diethyl ether (3×50mL). The combined ether extracts were dried (MgSO₄) and concentrated.Purification of the crude material by column chromatography on silicagel (20:1 CH₂Cl₂-EtOAc) provided 1.16 g (91%) of2-Hydroxy-4-methylbenzonitrile as a white solid. ¹H NMR (CDCl₃) δ2.36(s, 3H), 6.20 (br s, 1H), 6.79-6.81 (m, 2H), 7.38 (d, 1H, J=9 Hz).

[0226] To a solution of 2-Hydroxy-4-methylbenzonitrile (0.563 g, 4.23mmol) in CH₂Cl₂ (21 mL) was added acetic anhydride (0.60 mL, 6.36 mmol)followed by triethylamine (1.20 mL, 8.61 mmol) and the resultantsolution was stirred at room temperature for 30 minutes. The mixture wasdiluted with CH₂Cl₂ (60 mL), washed with saturated aqueous NaHCO₃ (20mL) and brine (2×20 mL). The organic phase was dried (Na₂SO₄) andconcentrated and provided 0.72 g (97%) of (2-cyano-5-methyl-phenyl)acetate as a white solid. ¹H NMR (CDCl₃) δ2.38 (s, 3H), 2.43 (s, 3H),7.08 (s, 1H), 7.13 (d, 1H, J=9 Hz), 7.54 (d, 1H, J=9 Hz).

[0227] To a solution of (2-cyano-5-methyl-phenyl) acetate (0.72 g, 4.11mmol) in CCl₄ (10 mL) was added recrystallized N-bromosuccinimide (0.767g, 4.31 mmol) followed by benzoyl peroxide (56 mg, 0.23 mmol). Theresultant mixture was heated to reflux for 2.5 hours then cooled to roomtemperature. The mixture was diluted with diethyl ether (50 mL),filtered through filter paper, and the filtrate was concentrated.Purification of the crude material by column chromatography (6:1hexanes-EtOAc) provided 0.31 g (30%) of (5-bromomethyl-2-cyano-phenyl)acetate as a colorless oil. ¹H NMR (CDCl₃) δ2.40 (s, 3H), 4.45 (s, 2H),7.33 (s, 1H), 7.35 (d, 1H, J=9 Hz), 7.65 (d, 1H, J=9 Hz).

[0228] To a solution of(1-tert-butoxycarbonyl-1H-Beenzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.375 g, 0.99 mmol) in CH₃CN (5 mL) was added N,N-diisopropylethylamine(0.35 mL, 2.00 mmol) followed by a solution of(5-bromomethyl-2-cyano-phenyl) acetate (0.318 g, 1.25 mmol) in CH₃CN (5mL). The resultant mixture was heated to 60° C. for 15 hours then cooledto room temperature. The mixture was concentrated and the residue waspartitioned between CH₂Cl₂ (40 mL) and brine (10 mL). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×10 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by column chromatography on silicagel (20:1 CH₂Cl₂—CH₃OH) followed by radial chromatography on silica gel(2 mm plate, 2:1 hexanes-EtOAc) provided 0.28 g (51%) of a tan foam.

[0229] The foam from above (0.28 g, 0.51 mmol) was dissolved in NH₃saturated methanol (10 mL), treated with Raney nickel (140 mg), andplaced under 50 psi H₂ on a Parr shaker for 17 hours. The mixture wasfiltered through Celite© and the cake was washed with methanol. Theeluant was concentrated under reduced pressure. Purification of thecrude material by column chromatography on silica gel (20:1:1CH₂Cl₂—CH₃OH—NH₄OH) followed by radial chromatography on silica gel (1mm plate, 100:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided 76 mg (33%) of the freebase of the title compound as a yellow foam.

[0230] Using General Procedure D: Conversion of the foam from above (72mg, 0.16 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD11071 (73 mg, 65%) asa white solid. ¹H NMR (D₂O) δ1.83-1.95 (m, 1H), 2.19-2.30 (m, 2H),2.40-2.45 (m, 1H), 3.02-3.04 (m, 2H), 3.55 (s, 2H), 3.72 (d, 1H, J=12.9Hz), 3.77 (d, 1H, J=12.9 Hz), 4.44 (d, 1H, J=16.2 Hz), 4.62 (d, 1H,J=16.2 Hz), 4.72-4.79 (m, 1H, overlaps with HOD), 6.61 (s, 1H), 6.72 (d,1H, J=7.8 Hz), 6.90 (d, 1H, J=7.8 Hz), 7.50-7.55 (m, 2H), 7.58-7.62 (m,2H), 7.92 (dd, 1H, J=6.0, 7.8 Hz), 8.40 (d, 1H, J=7.8 Hz), 8.74 (d, 1H,J=5.1 Hz); ¹³C NMR (D₂O) δ20.44, 20.88, 27.83, 38.85, 50.22, 56.74,63.17, 113.86, 116.57, 118.99, 122.04, 126.07, 126.69, 130.58, 131.10,139.63, 139.66, 140.96, 148.21, 150.83, 151.77, 154.96. ES-MS m/z 414(M+H). Anal. Calcd. for C₂₅H₂₇N₅O.3.1HBr.2.5H₂O: C, 42.33; H, 4.99; N,9.87; Br, 34.92. Found: C, 42.26; H, 4.94; N, 9.87; Br, 35.06.

EXAMPLE: 14

[0231]

AMD11077: Preparation of(4-Aminomethyl-3-methoxy-benzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0232] To a solution of 2-Hydroxy-4-methylbenzonitrile (0.46 g, 3.46mmol) in THF (17 mL) was added lithium hydroxide monohydrate (0.292 g,6.95 mmol) followed by dimethyl sulfate (0.50 mL, 5.28 mmol). Theresultant mixture was heated to reflux for 2 hours then cooled to roomtemperature. The mixture was diluted with diethyl ether (50 mL), washedwith saturated aqueous NaHCO₃ (3×15 mL), dried (MgSO₄) and concentrated.Purification of the crude material by column chromatography on silicagel (4:1 hexanes-EtOAc) provided 0.456 g (90%) of2-methoxy-4-methylbenzonitrile as a white solid. ¹H NMR (CDCl₃) δ2.41(s, 3H), 3.91 (s, 3H), 6.77 (s, 1H), 6.81 (d, 1H, J=6 Hz), 7.43 (d, 1H,J=6 Hz). ES-MS m/z 148 (M+H).

[0233] To a solution of 2-methoxy-4-methylbenzonitrile (0.438 g, 2.98mmol) in CCl₄ (6 mL) was added recrystallized N-bromosuccinimide (0.544g, 3.05 mmol) followed by benzoyl peroxide (47 mg, 0.19 mmol). Theresultant mixture was heated to reflux for 45 minutes then cooled toroom temperature. The mixture was diluted with diethyl ether (30 mL),filtered through filter paper, and the filtrate was concentrated.Purification of the crude material by column chromatography (6:1hexanes-EtOAc) provided 0.46 g (68%) of4-(bromomethyl)-2-methoxybenzonitrile as a white solid. ¹H NMR (CDCl₃)δ3.96 (s, 3H), 4.45 (s, 2H), 6.99 (s, 1H), 7.03 (d, 1H, J=9 Hz), 7.53(d, 1H, J=9 Hz).

[0234] To a solution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.386 g, 1.02 mmol) in CH₃CN (10 mL) was addedN,N-diisopropylethylamine (0.35 mL, 2.00 mmol) followed by of4-(bromomethyl)-2-methoxybenzonitrile (0.363 g, 1.60 mmol). Theresultant mixture was heated to 60° C. for 15 hours then cooled to roomtemperature. The mixture was concentrated and the residue waspartitioned between CH₂Cl₂ (40 mL) and brine (10 mL). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×10 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by column chromatography on silicagel (20:1 CH₂Cl₂—CH₃OH) followed by radial chromatography on silica gel(2 mm plate, 2:1 hexanes-EtOAc) provided 0.30 g (56%) of a white foam.

[0235] The foam from above (0.29 g, 0.55 mmol) was dissolved in NH₃saturated methanol (15 mL), treated with Raney nickel (300 mg), andplaced under 50 psi H₂ on a Parr shaker for 7 hours. The mixture wasfiltered through Celite© and the cake was washed with methanol. Theeluant was concentrated under reduced pressure. Purification of thecrude material by column chromatography on silica gel (10:1:1CH₂Cl₂—CH₃OH—NH₄OH) provided 0.197 g (83%) of the free base of the titlecompound as a white solid.

[0236] Using General Procedure D: Conversion of the solid from above(183 mg, 0.43 mmol) to the hydrobromide salt followed byre-precipitation of the intermediate solid from methanol/ether gaveAMD11077 (268 mg, 88%) as a white solid. ¹H NMR (D₂O) δ1.84-1.97 (m,1H), 2.20-2.31 (m, 2H), 2.43-2.50 (m, 1H), 3.03-3.06 (m, 2H), 3.55 (s,2H, 3.73 (s, 3H), 3.82 (d, 1H, J=12.6 Hz), 3.88 (d, 1H, J=12.6 Hz), 4.45(d, 1H, J=16.5 Hz), 4.63 (d, 1H, J=16.5 Hz), 4.72-4.79 (m, 1H, overlapswith HOD), 6.75 (s, 1H), 6.83 (d, 1H, J=7.5 Hz), 6.99 (d, 1H, J=7.5 Hz),7.50-7.54 (m, 2H), 7.57-7.61 (m, 2H), 7.93 (dd, 1H, J=6.0, 7.5 Hz), 8.40(d, 1H, J=8.1 Hz), 8.74 (d, 1H, J=6.0 Hz); ¹³C NMR (D₂O) δ20.46, 20.94,27.86, 39.08, 50.07, 55.62, 57.24, 63.25, 112.27, 113.78, 120.28,122.61, 126.16, 126.82, 130.47, 131.11, 139.65, 140.03, 141.06, 148.30,150.77, 151.78, 157.51. ES-MS m/z 428 (M+H). Anal. Calcd. forC₂₆H₂₂N₅O.3.0HBr.2.4H₂O: C, 43.77; H, 5.20; N, 9.82; Br, 33.60. Found:C, 43.61; H, 5.18; N, 9.45; Br, 33.88.

EXAMPLE: 15

[0237]

AMD9923: Preparation of(1H-benzoimidazol-2-ylmethyl)-(2,4-bis-aminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0238]

[0239] Preparation of 4-bromomethyl-isophthalonitrile

[0240] To a stirred solution of 4-methyl-isophthalonitrile (prepared asdescribed by Klement, I.; Lennick, K.; Tucker, C. E.; Knochel, P.Tetrahedron Lett. 1993, 34, 4623-4626) (500 mg, 3.52 mmol) in CCl₄ (4mL) was added solid N-bromosuccirimide (1.25 g, 7.0 mmol) followed bybenzoyl peroxide (8 mg, 0.04 mmol). The resulting mixture was heated toreflux for 8 h, at which time it was cooled to room temperature andconcentrated in vacuo. The crude material was purified by flashchromatography (silica gel, 4:1 hexanes-EtOAc) to give 457 mg of amixture 4-methyl-isophthalonitrile and 4-bromomethyl-isophthalonitrilein a 3:1 molar ratio, respectively. 4-Bromomethyl-isophthalonitriledisplayed ¹H NMR (CDCl₃) δ2.04 (s, 2H), 7.70-7.74 (m, 1H), 7.86-7.74 (m,1H), 7.96 (s, 1H).

[0241] Preparation of2-{[(2,4-dicyano-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

[0242] Following the General Procedure for N-alkylation, the 3:1 mixtureof mixture 4-methyl-isophthalonitrile and4-bromomethyl-isophthalonitrile obtained from the previous step (457 mg)and(1H-N-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(257 mg, 0.68 mmol) were converted into the corresponding alkylationproduct using the following quantities of reagents and solvents:diisopropylethylamine (237 μL, 1.36 mmol), CH₃CN (5 mL). The reactiontime in this case was 3 days, while the reaction temperature was 40° C.The resulting crude material was purified by flash chromatography(silica gel, 20:1:1 CH₂Cl₂—MeOH—NH₄OH) to provide 326 mg (93%) of2-{[(2,4-dicyano-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester. ¹H NMR (CDCl₃) δ1.73 (s, 9H), 1.75-2.20 (m, 3H),2.38-2.50 (m, 1H), 2.65-2.90 (m, 2H), 4.18 (d, 2H, J=6 Hz), 4.30-4.40(m, 1H), 4.53 (d, 1H, J=15 Hz), 4.70 (d, 1H, J=15 Hz), 7.02-7.04 (m,1H), 7.23-7.26 (m, 2H), 7.30-7.32 (m, 2H), 7.38 (s, 1H), 7.52-7.70 (m,2H), 7.85 (d, 1H, J=9 Hz), 8.45-8.50 (m, 1H).

[0243] Preparation of2-{[[2,4-Bis-(tert-butoxycarbonylamino-methyl)-benzyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester

[0244] A hydrogenation flask was charged with a 50% slurry of Raneynickel in water (300 mg), which was then washed with methanol (3×10 mL).A solution of2-{[(2,4-dicyano-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (326 mg, 0.63 mmol) in MeOH (10 mL) was thenadded, and NH₃ gas was bubbled through the solution for 5 min. Theresulting heterogeneous mixture was hydrogenated (50 psi) on a ParrShaker for 18 h; at this time, the crude mixture was filtered throughcelite, washed with MeOH (3×20 mL), and concentrated in vacuo. Flashchromatography (silica gel, 20:2:1 CH₂Cl₂—MeOH—NH₄OH, then 10:1MeOH—NH₄OH) of the resulting material afforded 124 mg (46%) of the freebase of AMD9923 as a white solid; however, combustion analysis revealedthat this material was contaminated with silica gel, and repeatedfiltration and chromatography (celite, florisil, silica gel, basicalumina) failed to remove the contaminant. Thus, this compound (60 mg,0.14 mmol) was taken up in a mixture of THF (5 mL), MeOH (1 mL) andwater (3 drops) then di-tert-butyl dicarbonate (92 mg, 0.42 mmol) wasadded. The resulting solution was stirred 2 h, at which point saturatedaqueous sodium bicarbonate (5 mL) was added, and the resulting mixturewas extracted with CH₂Cl₂ (3×10 mL) then the combined organic extractswere dried (MgSO₄), and concentrated in vacuo. Purification of the crudematerial thus obtained by radial chromatography (silica gel, 1 mm plate,50:1:1 CH₂Cl₂—MeOH—NH₄OH) afforded 71 mg (69%) of2-{[[2,4-bis-(tert-butoxycarbonylamino-methyl)-benzyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester as a colourless oil. ¹H NMR (CDCl₃) δ1.44 (s,18H), 1.53-1.54 (m, 1H), 1.69 (s, 9H), 1.99-2.04 (m, 1H), 2.17-2.29 (m,2H), 2.49-2.54 (m, 1H), 2.72-2.83 (m, 1H), 3.84-3.94 (m, 2H), 4.19 (d,2H, J=5 Hz), 4.28-4.54 (m, 6H), 4.68 (br s, 1H), 6.63 (dd, 1H, J=8, 5Hz), 6.70 (dd, 1H, J=18, 8 Hz), 7.17-7.24 (m, 3H), 7.36 (s, 1H),7.52-7.55 (m, 1H, 7.67-7.70 (m, 1H), 8.24 (d, 1H, J=4 Hz), 8.80 (br s,1H).

[0245] Following the general procedure D for concomitant BOCdeprotection and HBr salt formation, treatment of the oil from theprevious step (71 mg, 0.10 mmol) with HBr-saturated acetic acid (1 mL)afforded 48 mg (60%) of the HBr salt of AMD9923 as a white solid. ¹H NMR(CD₃OD) δ1.48-1.59 (m, 1H), 2.07-2.14 (m, 2H), 2.29-2.30 (m, 1H), 2.63(br d, 1H, J=17 Hz), 2.78-2.89 (m, 1H), 3.76 (d, 1H, J=14 Hz), 3.74-4.08(m, 7H), 4.16 (d, 1H, J=13 Hz), 6.99 (dd, 1H, J=8, 5 Hz), 7.16-7.20 (m,2H), 7.34-7.39 (m, 3H), 7.54-7.57 (m, 2H), 7.65 (s, 1H), 8.31 (d, 1H,J=5 Hz); ¹³C NMR (CD₃OD) δ21.3, 22.6, 22.8, 41.8, 43.6, 48.6, 55.7,60.9, 115.9, 123.4, 123.8, 130.9, 133.2, 134.2, 135.0, 135.8, 136.4,138.9, 140.2, 147.5, 152.8, 156.6. ES-MS m/z 427 (M+H). Anal. Calcd. forC₂₆H₃₀N₆.4HBr.1.5H₂O.0.7C₂H₄O₂: C, 40.17; H, 4.90; N, 10.26; Br, 39.01.Found: C, 40.13; H, 5.15; N, 10.20; Br, 39.08.

EXAMPLE: 16

[0246]

AMD11038: Preparation of5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid methyl ester (hydrobromide salt)

[0247] A solution of2-{[(4-cyano-2-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoimidazole-1-carboxylicacid tert-butyl ester (710 mg, 1.29 mmol) in saturated NH₃(g)/MeOH (25mL) was shaken at room temperature with a suspension of Raney® nickel(1.2 g) under hydrogen atmosphere (50 psi) for 17 h. The catalyst wasremoved by filtration over celite, and the filtrate was concentrated invacuo. The crude material was filtered through silica gel (20:1:1CH₂Cl₂/MeOH/NH₄OH) to give a white foam (416 mg, 71%).

[0248] Using General Procedure D: Conversion of the white foam fromabove (46 mg, 0.10 mmol) to the hydrobromide salt followed byre-precipitation of the intermediate solid from methanol/ether gaveAMD11138 (51 mg, 69%) as a colourless solid. ¹H NMR (D₂O) δ1.85-1.99 (m,1H), 2.17-2.37 (m, 2H), 2.40-2.49 (m, 1H), 3.04 (m, 2H), 3.62 (d, 1H,J=13.5 Hz), 3.75 (d, 1H, J=13.8 Hz), 3.94 (s, 3H), 4.10 (d, 1H, J=12.6Hz), 4.35 (d, 1H, J=12.6 Hz), 4.44 (d, 1H, J=16.2 Hz), 4.55 (d, 1H,J=16.2 Hz), 7.26 (dd, 1H, J=8.1, 1.8 Hz), 7.42 (d, 1H, J=8.1 Hz),7.50-7.61 (m, 5H), 7.92 (dd, 1H, J=7.8, 6.0 Hz), 8.40 (d, 1H, J=7.8 Hz),8.77 (d, 1H, J=5.1 Hz); ¹³C NMR (D₂O) δ20.52, 20.95, 27.80, 42.02,49.21, 53.44, 54.23, 63.26, 113.88, 126.10, 126.89, 130.46, 130.70,131.45, 132.75, 133.22, 133.67, 138.50, 139.66, 140.83, 148.14, 150.33,151.34, 168.79. ES-MS m/z 456 (M+H). Anal. Calcd. forC₂₇H₂₉N₅O₂.3.0HBr.2.2H₂O: C, 43.95; H, 4.97; N, 9.49; Br, 32.48. Found:C, 43.86; H, 4.97; N, 9.35; Br, 32.77.

EXAMPLE: 17

[0249]

AMD11163: Preparation of3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid hydrobromide salt

[0250] To a stirred solution of LiOH (41 mg, 1.7 mmol) in deionizedwater (2 mL) was added a solution of AMD11140 (77 mg, 0.17 mmol) in THF(2 mL). The mixture was heated to 50° C., stirred for 15 h, andconcentrated to remove THF. 1 N HCl (1.7 mL) was slowly added and theaqueous solution was extracted with CHCl₃ (3×10 mL). The combinedorganic extracts were dried over MgSO₄ and concentrated in vacuo. Thepale yellow solid (75 mg) was purified by flash column chromatography(1.5 cm i.d., 7 g silica gel, eluted with 10% NH₄OH/10% MeOH/CHCl₃) toafford the desired amino-acid as a white solid (32 mg).

[0251] A saturated solution of HBr in acetic acid (0.5 mL) was addeddropwise to a stirred solution of the amino-acid from above (30 mg,0.068 mmol) in acetic acid (0.5 mL) and stirring was continued for 1 h.Diethy ether (25 mL) was added quickly and the resultant whiteprecipitate was allowed to settle. The ether was decanted, the whitesolid was washed repeatedly with diethyl ether (5×25 mL), and theresidual ether was removed in vacuo. The residue was dried in a vacuumoven at 50° C. for 85 h to give AMD11163 as a white solid (35 mg, 28%over 2 steps). ¹H NMR(D₂O) δ1.81-2.01 (m, 1H), 2.20-2.35 (m, 2H),2.43-2.54 (m, 1H), 3.00-3.08 (m, 2H), 3.96 (d, 1H, J=15 Hz), 4.19-4.56(m, 5H), 4.76-4.92 (m, 1H, overlaps with HOD), 7.42-7.55 (m, 6H), 7.62(d, 1H, J=8.0 Hz), 7.91 (t, 1H, J=6.8 Hz), 8.38 (d, 1H, J=8.0 Hz), 8.75(d, 1H, 5.7 Hz); ¹³C NMR (D₂O) δ20.44, 21.15, 27.94, 40.03, 49.09,53.60, 63.12, 113.83 (2 carbons), 126.23, 127.06 (2 carbons), 130.39,130.53, 130.93, 131.85, 132.33, 140.23, 140.38, 141.18, 148.22, 150.33,150.58, 169.92. ES-MS m/z 442 (M+H). Anal. Calcd. forC₂₆H₂₇N₅O₂.3.0HBr.2.5H₂O: C, 42.82; H, 4.84; N, 9.60; Br, 32.87. Found:C, 42.74; H, 4.55; N, 9.51; Br, 32.53.

EXAMPLE: 18

[0252]

AMD11177: Preparation of 3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-N-hydroxy-benzamidehydrobromide salt

[0253] To a stirred solution of sodium metal (42 mg, 1.8 mmol) inanhydrous methanol (6 mL) was slowly added a solution of AMD11140 (159mg, 0.36 mmol) and hydroxylamine hydrochloride (75 mg, 1.1 mmol) inanhydrous methanol (6 mL). The mixture was heated to reflux, withstirring under a nitrogen atmosphere. After 16 h the solution wasconcentrated and the resultant residue was partitioned between CHCl₃ (15mL) and deionized H₂O (10 mL). The aqueous layer was extracted withCHCl₃ (10 mL) and the combined organic extracts were dried over MgSO₄and concentrated in vacuo. The pale yellow solid (185 mg) was purifiedby flash column chromatography (3 cm i.d., 15 g silica gel, eluted with10% NH₄OH/10% MeOH/CHCl₃) followed by radial chromatography (1 mm plate,eluted with 50:1:1 CH₂Cl₂/MeOH/NH₄OH) to afford the desiredhydroxy-amide as a white solid (63 mg).

[0254] A saturated solution of HBr in acetic acid (3 mL) was addeddropwise to a stirred solution of the hydroxy-amide from above (63 mg,0.11 mmol) in acetic acid (3 mL) and stirring was continued for 10 min.Diethy ether (50 mL) was added quickly and the resultant whiteprecipitate was allowed to settle. The ether was decanted, the whitesolid was washed repeatedly with diethyl ether (5×50 mL), and theresidual ether was removed in vacuo. The residue was dried in a vacuumoven at 50° C. for 42 h to give AMD11177 as a white solid (80 mg, 28%over 2 steps). ¹H NMR(D₂O) δ1.74-1.86 (m, 1H), 2.11-2.30 (m, 2H),2.35-2.44 (m, 1H), 2.85-2.93 (m, 2H), 3.96 (d, 1H, J=15 Hz), 4.12-4.39(m, 5H), 4.57-4.62 (m, 1H), 7.31 (s, 1H), 7.38-7.43 (m, 3H), 7.48-7.52(m, 3H), 7.59-7.64 (m, 1H), 8.03 (d, 1H, J=8.0 Hz), 8.56 (d, 1H, 5.7Hz); ¹³C NMR (D₂O) δ20.73, 21.28, 28.23, 40.14, 48.90,54.08, 62.97,114.15 (2 carbons), 124.98, 125.90 (2 carbons), 127.60, 128.81, 132.42,132.82, 139.26, 140.89, 142.38, 144.62. ES-MS m/z 457 (M+H). Anal.Calcd. for C₂₆H₂₈N₆O₂.3.2HBr.3.0H₂O.0.17NH₄Br: C, 39.72; H, 4.86; N,10.99; Br, 34.25. Found: C, 39.34; H, 4.78; N, 11.36; Br, 34.51.

EXAMPLE: 19

[0255]

AMD11180: Preparation of3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzamidehydrobromide salt

[0256] Preparation of3-cyano-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzamide

[0257] To a stirred solution of LiOH (120 mg, 5.0 mmol) in deionizedwater (5 mL) was added a solution of2-{[(2-cyano-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (273 mg, 0.49 mmol) in THF (5 mL). The mixture washeated to 50° C. and stirred for 17 h. The solution was cooled to roomtemperature, concentrated to remove THF, and neutralized with 1 N HCl.The aqueous solution was extracted with CHCl₃ (3×25 mL) and the combinedorganic extracts were dried over MgSO₄ and concentrated in vacuo to givethe desired acid as a yellow solid (224 mg).

[0258] A stirred solution of the acid from above (220 mg, 0.41 mmol) inCH₂Cl₂ (1.6 mL) was treated with oxalyl chloride (0.41 mL, 0.82 mmol)and heated to reflux for 1 h. The red solution was cooled to roomtemperature, then ammonia gas was bubbled through the stirred solutionfor 10 min. The crude mixture was poured into a saturated NaHCO₃solution, extracted with CHCl₃ (5×10 mL), and the combined organicextracts were dried over MgSO₄ and concentrated in vacuo. The orangefoam (200 mg) was purified by flash column chromatography (2 cm i.d., 10g silica, eluted with 5% NH₄OH/5% MeOH/CH₂Cl₂) to afford the titlecompound as an orange foam (106 mg, 50% over 2 steps). ¹H NMR(CDCl₃)δ1.70-1.93 (m br, 1H), 1.99-2.11 (m, 2H), 2.34-2.38 (m, 1H), 2.74-2.88(m, 2H), 3.88-3.99 (m, 2H), 4.13-4.28 (m, 3H), 5.70 (s br, 1H), 6.05 (sbr, 1H), 7.17-7.22 (m, 3H), 7.46 (d, 1H, J=7.5 Hz), 7.50-7.68 (m br,2H), 7.79-7.95 (m, 3H), 8.64 (d, 1H, J=3.0 Hz).

[0259] Preparation of3-aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzamidehydrobromide salt (AMD11180)

[0260] A solution of3-cyano-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzamide(105 mg, 0.24 mmol) in MeOH (10 mL) was treated with Raney nickel (50mg, cat.) and placed under 50 psi H₂ on a shaker for 3.5 h. The slurrywas filtered through diatomaceous earth, concentrated in vacuo, andpurified by flash column chromatography (3 cm i.d., 20 g silica, elutedwith 5% NH₄OH/5% MeOH/CH₂Cl₂) to afford the desired amide (35 mg).

[0261] A saturated solution of HBr in acetic acid (2 mL) was addeddropwise to a stirred solution of the amide from above (35 mg, 0.079mmol) in acetic acid (2 mL) and stirring was continued for 10 min.Diethy ether (50 mL) was added quickly and the resultant whiteprecipitate was allowed to settle. The ether was decanted, the whitesolid was washed repeatedly with diethyl ether (5×50 mL), and theresidual ether was removed in vacuo. The residue was dried in a vacuumoven at 50° C. for 17 h to give AMD11180 as a white solid (49 mg, 25%over 2 steps). ¹H NMR(D₂O) δ1.84-2.00 (m, 1H), 2.19-2.35 (m, 2H),2.46-2.54 (m, 1H), 3.00-3.08 (m, 2H), 3.97 (d, 1H, J=15 Hz), 4.21-4.58(m, 5H), 4.75-4.92 (m, 1H, overlaps with HOD), 7.40 (s, 1H), 7.44-7.55(m, 6H), 7.93 (t, 1H, J=6.8 Hz), 8.40 (d, 1H, J=8.0 Hz), 8.77 (d, 1H,5.5 Hz); ¹³C NMR (D₂O) δ20.43, 21.17, 27.94, 40.12, 49.11, 53.67, 63.17,113.83 (2 carbons), 126.33, 127.19 (2 carbons), 128.29, 129.24, 130.38,132.10, 132.51, 132.66, 139.96, 140.12, 141.33, 148.49, 150.15, 150.57,170.44. ES-MS m/z 441 (M+H). Anal. Calcd. forC₂₆H₂₈N₆O.3.3HBr.2.4H₂O.0.7NH₄Br: C, 38.11; H, 4.79; N, 11.45; Br,39.01. Found: C, 37.73; H, 4.64; N, 11.56; Br, 39.27.

EXAMPLE: 20

[0262]

AMD11190:3-Aminomethyl-4-{[(1H-benzimidazole-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid hydrazide (hydrobromide salt)

[0263] Preparation of(2-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}5hydrzinocarbonyl-benzyl)-carbamic acid tert-butyl ester

[0264] To a solution of4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-(tert-butoxycarbonylamino-methyl)-benzoicacid methyl ester (100 mg, 0.18 mmol) in ethanol (2 mL) was addedhydrazine hydrate (0.5 mL, 10.31 mmol). The reaction mixture was heatedto 80° C. overnight. Then it was cooled, quenched with saturated sodiumbicarbonate (2 mL), and washed with CH₂Cl₂ (4×5 mL). The combinedorganic layers were dried (Na₂SO₄), filtered, concentrated, and dried invacuo to afford a yellow oil. Purification by radial chromatography onsilica gel (1 mm plate, using CH₃-OH/NH₄OH/CH₂Cl₂; 1:1:98 then 2:1:97)to afford the product as a crude white solid (60 mg), which was usedwithout further purification. ¹H NMR (CDCl₃) δ1.55 (s, 9H), 1.61-1.71(m, 1H), 1.89-1.96 (m, 1H), 2.27 (br s, 3H), 2.35 (br m, 1H), 2.69-2.90(m, 2H), 3.80 (q, 2H, J=15 Hz), 3.92-4.04 (m, 4H), 4.41 (br m, 1H),7.11-7.18 (m, 3H), 7.18 (s, 1H), 7.28-7.42 (m, 3H), 7.60-7.61 (m, 1H),7.72 (s, 1H), 7.72 (br m, 1H), 8.66 (d, 1H, J=3.7 Hz). ES-MS m/z 557[M+H]⁺.

[0265] Preparation of3-Aminomethyl-4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)amino]-methyl}-benzoicacid hydrazide (hydrobromide salt)

[0266] To a solution of the above solid (30 mg, 0.054 mmol) in aceticacid (1 mL) was added a solution of hydrobromic acid in acetic acid (0.5mL) and the reaction mixture was stirred for 30 minutes. Then diethylether was added until a precipitation of AMD11190 was afforded as awhite solid (35 mg, 77%). ¹H NMR (D₂O) δ1.90-2.00 (m, 1H), 2.23-2.34 (m,2H), 2.48-2.52 (m, 1H), 3.04 (br s, 2H), 3.98 (d, 1H, J=13.8 Hz), 423(d, 1H, J=7.5 Hz), 4.29 (t, 1H, J=8.7 Hz), 4.38 (s, 1H), 4.45 (s, 1H),4.51 (d, 1H, J=6.0 Hz), 4.57 (s, 1H), 7.43-7.54 (m, 7H), 7.92 (t, 1H,J=7.5 Hz), 8.40 (d, 1H, J=7.8 Hz), 8.75 (d, 1H, J=5.1 Hz). ¹³C NMR (D₂O)δ20.40, 21.09, 27.91, 39.99, 48.94, 53.55, 62.94, 113.90, 126.31,127.04, 128.04, 129.15, 130.45, 132.47, 140.11, 140.65, 141.31, 148.47,150.13, 150.53. ES-MS m/z 456 {M+H]⁺. Anal. Calcd. forC₂₆H₂₉N₇O.4.0HBr.3.6H₂O: C, 37.00; H, 4.80; N, 11.62; Br, 37.87. Found:C, 37.18; H, 4.64; N, 11.31; Br, 37.91.

EXAMPLE: 21

[0267]

AMD11175: Preparation of(2-aminomethyl-5-fluorobenzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0268] Preparation of 4-fluoro-2-methylbenzonitrile

[0269] A solution of CuCN (4.45 g, 50.0 mmol) and NaCN (3.91 g, 80.0mmol) in H₂O (15 mL) was heated to 60° C. A suspension of4-fluoro-2-methylaniline (5.16 g, 41.2 mmol) in H₂O (20 mL) wasacidified with concentrated HCl (10 mL). Additional H₂O (approx. 50 mL)was added until the resulting suspension stirred freely and the mixturewas cooled to below 0° C. with an ice/salt water bath. A solution ofNaNO₂ (3.19 g, 46.2 mmol) in H₂O (8 mL) was added dropwise along withcrushed ice, ensuring that ice was always present in the diazonium saltsolution. The mixture was stirred at 0° C. for 15 minutes, then powderedK₂CO₃ (6.62 g, 47.9 mmol) was added portionwise to neutralize thesolution. The resulting bright orange solution was then addedportionwise to the 60° C. cyanide solution over approx. 40 minutes. Theresulting green suspension was heated to 110° C. for 45 minutes and,once cooled to room temperature, saturated aqueous NaHCO₃ (80 mL) wasadded. Extraction of this thick, black solution with CH₂Cl₂ (150 mL×3)did not yield any desired material.

[0270] An orange solid that was found to have sublimed in the condenserduring the reflux portion of the reaction was rinsed out with CH₂Cl₂(100 mL) and washed with H₂O (50 mL). The aqueous solution was extractedwith CH₂Cl₂ (25 mL×2) and the combined organic solution was dried(MgSO₄), filtered and concentrated under reduced pressure, affording thenitrile as a yellow solid (3.00 g, 22.2 mmol, 54%). ¹H NMR (CDCl₃) δ2.55(s, 3H), 6.94-7.04 (m, 2H), 7.60 (dd, 1H, J=8.6, 5.6 Hz). IR (thin film,KBr) ν 2223 cm⁻¹.

[0271] Preparation of 2-bromomethyl-4-fluorobenzonitrile

[0272] To a solution of the o-tolunitrile (1.62 g, 12.0 mmol) in benzene(80 mL) was added NBS (1.33 g, 7.47 mmol) and AIBN (153 mg, 0.93 mmol).The solution was heated at reflux under nitrogen for 3 hours and asecond portion of each of NBS (1.25 g, 7.02 mmol) and AIBN (150 mg, 0.91mmol) were added. The reaction was heated at reflux for a further 2hours and, once cooled, the solution was washed with H₂O (80 mL×2) andbrine (80 mL). The organic solution was dried (MgSO₄), filtered andconcentrated under reduced pressure. Purification by flash columnchromatography on silica (EtOAc/hexane, 1:9) gave the bromide as anorange solid (721 mg, 3.37 mmol, 28%). ¹H NMR (CDCl₃) δ4.60 (s, 2H),7.13 (td, 1H, J=8.2, 2.5 Hz), 7.28 (dd, 1H, J=8.9, 2.6 Hz), 7.69 (dd,1H, J=8.6, 5.3 Hz).

[0273] Preparation of2-{[(2-cyano-5-fluorobenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester

[0274] A solution of the benzyl bromide (263 mg, 1.23 mmo),(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(381 mg, 1.01 mmol), DIPEA (0.26 mL, 1.5 mmol), and KI (10 mg, 0.06mmol) in CH₃CN (7 mL) was stirred at 60° C. under nitrogen for 17 hours.Once cooled to room temperature, saturated aqueous NaHCO₃ (10 mL) wasadded and the mixture was extracted with CH₂Cl₂ (25 mL×3). The combinedorganic solution was dried (MgSO₄), filtered and concentrated underreduced pressure. Purification by flash column chromatography on silica(EtOAc/hexane, 1:1) gave the tertiary amine as a pale yellow foam (411mg, 0.80 mmol, 80%). ¹H NMR (CDCl₃) δ1.75 (s, 9H), 1.85-2.11 (m, 3H),2.31-2.41 (m, 1H), 2.64-2.92 (m, 2H), 4.03 (d, 1H, J=16.2 Hz), 4.18 (d,1H, J=16.2 Hz), 4.34 (dd, 1H, J=10.2, 5.7 Hz), 4.62 (d, 1H, J=14.1 Hz),4.74 (d, 1H, J=14.1 Hz), 6.55 (td, 1H, J=8.1, 2.7 Hz), 7.00 (dd, 1H,J=7.7, 4.7 Hz), 7.14 (dd, 1H, J=8.4, 5.4 Hz), 7.20 (dd, 2H, J=6.2, 3.2Hz), 7.23-7.31 (m, 1H), 7.56-7.66 (m, 3H), 8.44 (dd, 1H, J=4.5, 1.2 Hz).

[0275] Preparation of2-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-4-fluorobenzonitrile

[0276] To LiOH H₂O (51 mg, 1.2 mmol) and 10% Pd/C (39 mg, 0.04 mmol) ina 50 mL round bottom flask flushed with nitrogen was added H₂O (2 mL). Asolution of the nitrile (201 mg, 0.39 mmol) in dioxane (6 mL) was addedfollowed by Raney-Ni (0.07 mL, 0.6 mmol) as a 50% suspension in H₂O (asdescribed by Klenke, B.; Gilbert, I. H. J. Org. Chem. 2001, 66,2480-2483). The flask was flushed with H₂ and heated to 45° C. for 15hours. Once cooled to room temperature and flushed with nitrogen, themixture was filtered through Celite, washing with EtOAc. The filtratewas concentrated under reduced pressure, the residue was taken up intosaturated aqueous NaHCO₃ (15 mL) and extracted with CH₂Cl₂ (25 mL×3).The organic solution was dried (MgSO₄), filtered and evaporated underreduced pressure, giving the free benzimidazole as a pale yellow solid(153 mg, 0.37 mmol, 95%). ¹H NMR (CDCl₃) δ1.63-1.78 (m, 1H), 1.93-2.13(m, 3H), 2.30-2.42 (m, 1H), 2.69-2.90 (m, 2H), 3.88 (d, 1H, J=14.9 Hz),3.93 (d, 1H, J=14.9 Hz), 4.09-4.13 (m, 1H), 4.21 (d, 1H, J=16.1 Hz),4.28 (d, 1H, J=16.1 Hz), 6.95 (td, 1H, J=8.3, 2.6 Hz), 7.18-7.22 (m,3H), 7.45-7.57 (m, 3H), 7.63-7.67 (m, 2H), 8.67 (dd, 1H, J=4.8, 1.5 Hz).

[0277] Preparation of AMD11175

[0278] The nitrile (153 mg, 0.37 mmol) in a solution of MeOH saturatedwith NH₃ (10 mL) was hydrogenated over Raney-Ni at 50 psi for 4 hours.The mixture was filtered through Celite, washed with MeOH, and thefiltrate was concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.1 then9:1:0.05) gave the primary amine as a white solid (44 mg, 0.11 mmol,29%), along with recovered nitrile (24 mg, 0.06 mmol, 16%).

[0279] To the amine (42 mg, 0.10 mmol) in glacial HOAc (1 mL) was addeda saturated solution of HBr in HOAc (0.5 mL) and the solution wasstirred at room temperature for 30 minutes. Et₂O (5 mL) was added, theprecipitate was allowed to settle and the solvent was decanted. Theprecipitate was washed with Et₂O (1 mL×5) and dried at 90° C. underreduced pressure giving AMD11175 as a beige solid (66 mg, 0.095 mmol,95%). ¹H NMR (D₂) δ1.82-1.97 (m, 1H), 2.17-2.36 (m, 2H), 2.41-2.53 (m,1H), 2.98-3.08 (m, 2H), 3.91 (d, 1H, J=13.8 Hz), 4.16 (d, 2H, J=13.8Hz), 4.32-4.38 (2×d, 2H, J=16.2 and 13.8 Hz), 4.54 (d, 1H, J=16.2 Hz),6.68 (td, 1H, J=8.6, 2.7 Hz), 7.04 (dd, 1H, J=8.4, 6.0 Hz), 7.19 (dd,1H, J=9.9, 2.4 Hz), 7.51-7.55 (m, 2H), 7.60-7.63 (m, 2H), 7.89 (t, 1H,J=6.8 Hz), 8.37 (d, 1H, J=7.8 Hz), 8.72 (d, 1H, J=5.4 Hz). ¹³C NMR (D₂O)δ20.4, 20.9, 27.9, 39.5, 48.7, 53.3, 62.2, 113.9, 116.1 (d, J=21.7 Hz),118.1 (d, J=22.0 Hz), 126.2, 127.0, 127.6, 130.7, 132.5 (d, J=8.7 Hz),138.1, 140.2, 141.1, 148.2, 150.5 (d, J=20.9 Hz). ¹⁹F NMR (D₂O)δ35.9ES-MS m/z 416 (M+H). Anal. Calcd. for C₂₅H₂₆FN₅.3.0HBr.2.3H₂O: C,42.92; H, 4.84; N, 10.01; Br, 343.26. Found: C, 43.00; H, 4.85; N, 9.71;Br, 34.37.

EXAMPLE: 22

[0280]

AMD11140: Preparation of3-aminomethyl-4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid methyl ester

[0281] Preparation of 4-bromomethyl-3-cyano-benzoic acid methyl ester

[0282] A suspension of zinc dust (792 mg, 12.12 mmol) and1,2-dibromoethane (44 μL, 0.51 mmol) in THF (3 mL) was stirred at 70° C.for 10 minutes. The mixture was cooled to room temperature andchlorotrimethylsilane (45 μL, 0.36 mmol) was added. The mixture wascooled to 0° C. and a solution of methyl-4(bromomethyl)benzoate (2.314g, 10.10 mmol) in THF (11 mL) was added at 0° C. over 2 hours and thenstirred for an additional 2 hours at 0° C. The reaction mixture wascooled to −78° C. and a solution of tosyl cyanide (1.556 g, 8.59 mmol)in THF (11 mL) was added and the resultant mixture stirred at roomtemperature for 16 hours. The mixture was concentrated under reducedpressure, diluted with CH₂Cl₂ (100 mL) and saturated aqueous NaHCO₃ (15mL) and filtered. The phases were separated and the aqueous layer wasextracted with CH₂Cl₂ (3×50 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated under reduced pressure.Purification by column chromatography on silica gel (Hexanes/EtOAc,10:1) afforded the desired nitrile (973 mg) as a 16:1 mixture (desiredproduct/side product).

[0283] A solution of the nitrile from above (973 mg), N-bromosuccinimide(1.087 g, 6.11 mmol) and AIBN (137 mg, 0.83 mmol) in CCl₄ (18.5 mL) washeated to reflux for 4 days. The reaction mixture was cooled to roomtemperature, filtered and concentrated under reduced pressure.Purification of the yellow syrup by column chromatography on silica gel(Hexanes/EtOAc, 20:1 then 40:3) afforded the desired bromide (800 mg,37% over 2 steps) as a white solid. ¹H NMR (CDCl₃) δ3.96 (s, 3H), 4.66(s, 2H), 7.65 (d, 1H, J=8.1 Hz), 8.23 (dd, 1H, J=8.1, 1.8 Hz), 8.33 (d,1H, J=1.5 Hz).

[0284] Preparation of2-{[(2-cyano-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester

[0285] A solution of 4-bromomethyl-3-cyano-benzoic acid methyl ester(800 mg, 3.15 mmol),2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzimidazole-1-carboxylicacid tert-butyl ester (1.253 g, 3.15 mmol), KI (26 mg, 0.16 mmol) andDIPEA (0.82 mL, 4.72 mmol) in CH₃CN (31.5 mL) was heated at 60° C.overnight. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The resultant brown syrup wasdiluted with CH₂Cl₂ (100 mL) and washed with saturated aqueous NaCl (30mL). The aqueous phase was extracted with CH₂Cl₂ (2×50 mL) and thecombined organic extracts were dried (MgSO₄), filtered and concentratedunder reduced pressure. Purification of the brown foam by columnchromatography on silica gel (CH₂Cl₂/MeOH, 20:1) afforded the desiredmethyl ester (1.74 g, 100%) as a beige foam. ¹H NMR (CDCl₃) δ1.69-1.78(m, 10H), 1.95-2.09 (m, 2H), 2.36-2.41 (m, 1H), 2.63-2.85 (m, 2H), 3.86(s, 3H), 4.17 (d, 1H, J=16.2 Hz), 4.20 (d, 1H, J=15.9 Hz), 4.35-4.40 (m,1H), 4.58 (d, 1H, J=14.4 Hz), 4.69 (d, 1H, J=14.4 Hz), 7.01 (dd, 1H,J=7.8, 4.8 Hz), 7.13-7.23 (m, 2H), 7.31 (d, 1H, J=7.5 Hz), 7.55-7.61 (m,2H), 7.76 (d, 2H, J=1.2 Hz), 7.87 (s, 1H), 8.44 (d, 1H, J=4.5 Hz).

[0286]2-{[(2-Cyano-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (1.23 g, 2.23 mmol) was dissolved in NH₃ saturatedMeOH (˜15 mL), treated with Raney nickel (excess), and placed under 45psi H₂ on a Parr shaker for 16 hours. The mixture was diluted with MeOHand filtered through Celite. The cake was washed with MeOH and thecombined filtrate was concentrated under reduced pressure. The resultantsyrup was filtered through a silica gel plug (CH₂Cl₂/MeOH/NH₄OH,100:2:1) to afford the desired amine (720 mg) that was used withoutfurther purification in the next reaction.

[0287] To a solution of the amine from above (64 mg) in CH₂Cl₂ (1 mL)was added TFA (1 mL) and the resultant mixture was stirred at roomtemperature overnight. The mixture was concentrated under reducedpressure and the resultant syrup was dissolved in H₂O and basified with1N NaOH (pH 8). CHCl₃ (75 mL) was added, the phases were separated andthe aqueous layer was extracted with CHCl₃ (2×75 mL). The combinedorganic extracts were dried (MgSO₄), filtered and concentrated underreduced pressure. Purification of the yellow foam by radialchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 100:1:1 then 200:3:1)afforded AMD11140 (39 mg, 43% over 2 steps) as a white foam. ¹H NMR(CDCl₃) δ1.55-1.73 (m, 1H), 1.92-2.07 (m, 2H), 2.23-2.35 (m, 1H),2.63-2.89 (m, 2H), 3.74-4.02 (m, 10H), 7.06 (dd, 1H, J=7.5, 4.8 Hz),7.16-7.19 (m, 2H), 7.35 (d, 1H, J=7.5 Hz), 7.47 (d, 1H, J=7.8 Hz), 7.57(br s, 2H), 7.79-7.82 (m, 1H), 7.93 (br s, 1H), 8.49 (d, 1H, J=3.9 Hz);¹³C NMR (CDCl₃) δ21.75, 22.72, 29.47, 43.47, 49.67, 52.47, 53.72, 60.08,122.16, 122.49, 128.59, 130.22, 131.01, 131.25, 135.03, 137.53, 142.15,142.66, 147.34, 154.59, 156.99, 167.19. ES-MS m/z 456.4 (M+H). Anal.Calcd. for C₂₇H₂₉N₅O₂.1.0H₂O: C, 68.48; H, 6.60; N, 14.79. Found: C,68.54; H, 6.52; N, 14.51.

EXAMPLE: 23

[0288]

AMD11158: Preparation of(2-aminomethyl-4-methoxymethyl-benzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0289] Preparation of2-{[[2-(tert-butoxycarbonylamino-methyl)-4-hydroxymethyl-benzyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester

[0290]2-{[(2-Aminomethyl-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (1.23 g, 2.23 mmol) was dissolved in NH₃ saturatedMeOH (15 mL), treated with Raney nickel (excess), and placed under 45psi H₂ on a Parr shaker for 16 hours. The mixture was diluted with MeOHand filtered through Celite. The cake was washed with MeOH and thecombined filtrate was concentrated under reduced pressure. The resultantsyrup was filtered through a silica gel plug (CH₂Cl₂/MeOH/NH₄OH,100:2:1) to afford the desired amine (720 mg) that was used withoutfurther purification in the next reaction.

[0291] To a solution of the amine from above (500 mg) in THF (7.2 mL)cooled to 0° C. was added LiAlH₄ (1.0 M in THF, 1.80 mL, 1.80 mmol)dropwise. The mixture was stirred at room temperature for 15 minutes.MeOH (2 mL) was added and the mixture concentrated and this was repeatedtwice more. The light yellow foam (410 mg) was used in the next reactionwithout further purification.

[0292] To a solution of the alcohol from above (330 mg) in THF (2 mL)was added a solution of BOC₂O (205 mg, 0.94 mmol) in THF (4 mL) and theresultant mixture was stirred at room temperature for 3 days. Thereaction mixture was concentrated under reduced pressure. Purificationof the yellow foam by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 100:2:1) afforded the desired amine (230 mg, 30%over 3 steps) as a light yellow foam. ¹H NMR (CDCl₃) δ1.44 (s, 9H),1.65-1.70 (m, 10H), 1.96-2.08 (m, 1H), 2.16-2.27 (m, 2H), 2.46-2.57 (m,1H), 2.71-2.85 (m, 1H), 3.86-3.97 (m, 2H), 4.31 (d, 1H, J=15.0 Hz),4.38-4.48 (m, 2H), 4.54-4.59 (m, 4H), 6.63 (dd, 1H, J=7.2, 4.5 Hz), 6.98(d, 1H, J=7.8 Hz), 7.13-7.24 (m, 4H), 7.45 (s, 1H), 7.53-7.56 (m, 1H),7.68-7.71 (m, 1H), 8.24 (d, 1H, J=3.9 Hz), 8.82-8.87 (m, 1H).

[0293] A solution of2-{[[2-(tert-butoxycarbonylamino-methyl)-4-hydroxymethyl-benzyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (230 mg, 0.37 mmol) and NaH (60% dispersion inmineral oil, 13.3 mg, 0.56 mmol) in DMF (2.0 mL) was stirred at roomtemperature for 30 minutes. Iodomethane (0.12 mL, 1.85 mmol) was addedand the resultant mixture was stirred at room temperature for 1 hour.The mixture was concentrated in vacuo, diluted with EtOAc and washedconsecutively with saturated aqueous NaHCO₃ (2×5 mL) and saturatedaqueous NaCl (10 mL). The organic layer was dried (MgSO₄) andconcentrated under reduced pressure. Purification of the yellow foam bycolumn chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 200:1:1 then200:2:1) afforded the desired product (97 mg) which was used in the nextreaction without further purification.

[0294] To a solution of the amine from above (96 mg) in CH₂Cl₂ (1 mL)was added TFA (1 mL) and the resultant mixture was stirred at roomtemperature overnight. The mixture was concentrated under reducedpressure and the syrup was dissolved in H₂O and basified with 1N NaOH(pH 8). CHCl₃ (75 mL) was added, the phases were separated and theaqueous layer was extracted with CHCl₃ (2×75 mL). The combined organicextracts were dried (MgSO₄), filtered and concentrated under reducedpressure. Purification of the yellow foam by radial chromatography onsilica gel (CH₂Cl₂/MeOH/NH₄OH, 100:1:1 then 200:3:1) afforded AMD11158(20.2 mg, 13% over 2 steps) as a white solid. ¹H NMR (CD₃OD) δ1.52-1.66(m, 1H), 2.04-2.25 (m, 3H), 2.61-2.71 (m, 1H), 2.82-2.93 (m, 1H),3.60-3.65 (m, 1H), 3.72-3.75 (m, 4H), 3.81 (d, 1H, J=12.9 Hz), 3.91-3.98(m, 3H), 4.13 (d, 1H, J=13.2 Hz), 4.53 (s, 2H), 7.02 (dd, 1H, J=7.5, 4.5Hz), 7.14-7.27 (m, 4H), 7.33-7.40 (m, 3H), 7.54-7.56 (m, 1H), 8.32-8.36(m, 1H); ¹³C NMR (CD₃OD) δ23.27, 23.34, 30.59, 31.18, 44.23, 48.33,55.77, 60.96, 65.21, 111.37, 119.67, 123.44, 123.69, 124.30, 127.17,130.03, 132.72, 136.74, 136.87, 138.48, 142.81, 143.24, 148.08, 153.81,158.22. ES-MS m/z 442.4 (M+H). Anal. Calcd. forC₂₇H₃₁N₅O.1.2CH₄O.0.2CH₂Cl₂: C, 68.63; H, 7.34; N, 14.09. Found: C,69.03; H, 7.09; N, 13.79.

EXAMPLE: 24

[0295]

AMD9852: Preparation ofN-(2-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzyl)-guanidine

[0296] To a solution of(1H-Benzimidazol-2-ylmethyl)-(2-Aminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(see AMD9720) (50 mg, 0.125 mmol) in THF (5 mL) was added addedN,N′-di-t-butoxycarbonyl-pyrazole-1-carboxamidine (60 mg, 0.187 mmol)and potassium carbonate (35 mg, 0.25 mmol) and the mixture stirredovernight. The reaction was diluted with aqueous NH₄Cl (5 mL) andextracted with ethyl acetate (3×10 mL). The combined organic fractionswere dried (Na₂SO₄), concentrated and purified by chromatography onsilica gel (5% MeOH/CH₂Cl₂) to give the desired product as a pale foam(51 mg, 64%). 1H NMR (CDCl₃) δ1.47 (s, 9H), 1.48 (s, 9H), 1.81 (m, 1H),2.00 (m, 2H), 2.26 (m, 2H), 2.71-2.88 (m, 2H), 3.89-4.05 (m, 5H), 4.73(dd, 1H, J=15.5, 5.1 Hz), 4.96 (dd, 1H, J=15.5, 5.7 Hz), 7.12 (m, 7H),7.36-7.44 (m, 3H), 7.55 (br s, 1H (NH)), 8.55 (m, 1H (NH)), 8.66 (d, 1H,J=5.1 Hz).

[0297] Using General Procedure D: Conversion of the foam from above (51mg, 0.08 mmol) to the hydrobromide salt gave AMD9852 as a white solid(108 mg). ¹H NMR (D₂O). δ1.88 (m, 1H), 2.21 (m, 2H), 2.43 (m, 1H), 3.01(m, 2H), 3.81 (d, 1H, J=13.5 Hz), 4.01 (d, 1H, J=13.5 Hz), 4.34 (d, 1H,J=16.2 Hz), 4.38 (d, 1H, J=14.4 Hz), 4.44 (d, 1H), J=14.4 Hz), 4.55 (d,1H, J=16.2 Hz), 4.78 (m, 1H), 6.99 (m, 2H), 7.10 (dt, 1H, J=7.2, 1.2Hz), 7.40 (d, 1H, J=6.9 Hz), 7.55 (m, 2H), 7.62 (m, 2H), 7.87 (dd, 1H,J=7.8, 5.7 Hz), 8.35 (d, 1H, J=7.8 Hz), 8.68 (d, 1H, J=5.1 Hz). ¹³C NMR(D₂O) δ18.03, 18.26, 25.51, 40.78, 46.69, 50.49, 59.14, 111.69 (2C),123.74, 124.50 (2C), 126.48, 126.65, 126.74, 128.35, 128.98, 132.04,137.48, 138.22, 145.85, 150.02. ES-MS m/z 440 (M+H); Anal. Calcd. for(C₂₆H₂₉N₇×3.0 HBr×3.0 H₂O): C, 42.41; H, 5.07; N, 13.32; Br 32.55.Found: C, 42.67; H, 5.07; N, 13.24; Br, 32.77.

EXAMPLE: 25

[0298]

AMD9596: Preparation ofN-(4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzyl)-guanidine(hydrobromide salt)

[0299] To a solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(397 mg, 1.0 mmol) in THF (10 mL) was addedN,N′-di-t-butoxycarbonyl-pyrazole-1-carboxamidine (370 mg, 1.2 mmol) andpotassium carbonate (207 mg, 1.5 mmol) and the mixture stirred at roomtemperature for 16 h. The reaction was diluted with aqueous NH₄Cl (15mL) and the mixture extracted with ethyl acetate (3×10 mL). The combinedorganic fractions were dried (Na₂SO₄), filtered, concentrated andpurified by chromatography on silica gel (19:1 CH₂Cl₂/MeOH) to affordN′,N″-di-t-butoxycarbonyl-N-(4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzyl)-guanidineas a pale foam (426 mg, 67%). ¹H NMR (CDCl₃) δ1.25 (s, 9H), 1.44 (s,9H), 1.65 (m, 1H), 1.99 (m, 2H), 2.04 (m, 1H), 2.72-2.79 (m, 2H), 3.73(s, 2H), 3.94 (d, 1H, J=16.1 Hz), 4.07 (m, 1H), 4.11 (d, 1H, J=16.1 Hz),4.51 (d, 2H, J=6.2 Hz), 7.14 (m, 4H), 7.39 (m, 3H), 7.55 (m, 1H), 7.63(m, 1H), 8.47 (m, 1H (NH)), 8.66 (d, 1H, J=4.8 Hz).

[0300] Using General Procedure D: Conversion of the material from above(106 mg, 0.1 mmol) to the hydrobromide salt with simultaneous removal ofthe Boc groups gave AMD 9596 (108 mg) as a white crystalline solid. ¹HNMR (D₂O). δ1.88 (m, 1H), 2.21 (m, 2H), 2.43 (m, 1H), 3.01 (m, 2H), 3.78(d, 1H, J=12.6 Hz), 3.83 (d, 1H, J=12.6 Hz), 3.89 (s, 2H), 4.45 (d, 1H,J=16.5 Hz), 4.60 (d, 1H, J=16.5 Hz), 4.79 (m, 1H), 6.89 (d, 2H, J=7.8Hz), 7.15 (d, 2H, J=7.8 Hz), 7.50 (m, 2H), 7.57 (m, 2H), 7.91 (dd, 1H,J=8.1, 6.0 Hz), 8.39 (d, 1H, J=8.1 Hz), 8.73 (d, 1H, J=6.0 Hz). ¹³C NMR(D₂O) δ20.46, 20.87, 27.83, 43.90, 50.31, 56.69, 63.17, 113.76 (2C),126.04, 126.62 (2C), 127.03 (2C), 130.52 (2C), 135.98, 136.24, 139.58,140.92, 148.20, 150.93, 151.86. ES-MS m/z 440 (M+H); Anal. Calcd. for(C₂₆H₂₉N₇×3.2 HBr×2.2 H₂O): C, 42.31; H, 5.00; N, 13.28; Br 33.64.Found: C, 42.48; H, 5.05; N, 13.15; Br, 32.64.

EXAMPLE: 26

[0301]

AMD9735: Preparation ofN′-(4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-N,N-dimethyl-guanidine(hydrobromide salt)

[0302] Preparation of N,N-dimethyl-1H-pyrazole-1-carboxamidinehydrochloride

[0303] To a solution of pyrazole (1.01 g, 14.8 mmol) anddimethylcyanamide (1.20 mL, 14.8 mmol) in 1,4-dioxane (15 mL) was addedHCl (4.0 N in 1,4-dioxane, 3.8 mL, 15.2 mmol) and the resultant mixturewas heated to reflux for 3 hours. The reaction mixture was cooled toroom temperature and diluted with dry ether (15 mL) to precipitate ayellow solid. The resultant precipitate was allowed to settle to thebottom of the flask (overnight) and the supernatant solution wasdecanted. The solid was dried under vacuum and provided the titlecompound (2.01 g, 78%). ES-MS m/z 139 (M+H).

[0304] To a solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.221 g, 0.56 mmol) in DMF (1 mL) was addedN,N-dimethyl-1H-pyrazole-1-carboxamidine hydrochloride (0.250 g, 1.18mmol) and N,N-diisopropylethylamine (0.70 mL, 4.02 mmol) and theresultant mixture was stirred at room temperature for 19 h. The reactionmixture was diluted with water (5 mL) and CH₂Cl₂ (25 mL) and the pH ofthe aqueous phase was adjust to ˜4 using dilute aqueous HCl (1 N, 3 mL).The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (3×10 mL). The aqueous phase was concentrated under reducedpressure and the resultant colorless oil was dissolved in 10 N NaOH (4mL). The basic aqueous solution was extracted with CH₂Cl₂ (4×10 mL) andthe combined organic extracts were dried (Na₂SO₄) and concentrated. Thecrude material was purified by radial chromatography on silica gel (1 mmplate, 1:1:1 CH₃CN-CH₃OH-NH₄OH) and provided a white solid (147 mg).

[0305] Using General Procedure D: Conversion of the free base (124 mg)to the hydrobromide salt, followed by re-precipitation of theintermediate solid from methanol/ether, gave AMD9735 (121 mg) as a whitesolid. ¹H NMR (D₂O) δ1.84-1.98 (m, 1H), 2.20-2.34 (m, 2H), 2.40-2.47 (m,1H), 2.99-3.06 (m, 8H), 3.77 (d, 1H, J=12.6 Hz), 3.84 (d, 1H, J=12.6Hz), 3.96 (s, 2H), 4.47 (d, 1H, J=16.5 Hz), 4.65 (d, 1H, J=16.5 Hz),4.72-4.79 (m, 1H, overlaps with HOD), 6.93 (d, 2H, J=7.8 Hz), 7.18 (d,2H, J=7.8 Hz), 7.50-7.53 (m, 2H), 7.58-7.63 (m, 2H), 7.93 (dd, 1H,J=6.6, 7.2 Hz), 8.39 (d, 1H, J=7.8 Hz), 8.77 (d, 1H, J=5.7 Hz); ¹³C NMR(D₂O) δ20.29, 20.70, 27.67, 37.99, 44.43, 50.09, 56.39, 62.91, 113.65,125.86, 126.39, 126.86, 130.33, 130.36, 135.80, 136.43, 139.47, 140.75,148.01, 150.75, 151.75, 155.99; ES-MS m/z 468 (M+H). Anal. Calcd. forC₂₈H₃₃N₇.3.2 HBr.2.6 H₂O.1.4 NH₄Br: C, 36.94; H, 5.20; N, 12.92; Br,40.37. Found: C, 36.94; H, 5.06; N, 12.88; Br, 40.45.

EXAMPLE: 27

[0306]

AMD9777: Preparation of[4-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-aminomethylbenzyl]-N,N-dimethylformamidine(hydrobromide salt)

[0307] A solution of 2-pyridine sulfonyl chloride (41 mg, 0.23 mmol) inDMF (0.75 mL) was stirred for 10 min after which time a solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(62 mg, 0.16 mmol) in DMF (0.8 mL) was added and the reaction stirred atroom temperature for 3 h. The reaction was concentrated under reducedpressure and diluted with CH₂Cl₂ (5 mL) and saturated aqueous K₂CO₃ (5mL). The layers were separated and the organic phase dried (MgSO₄),filtered, concentrated and purified by column chromatography on silicagel (5% MeOH/CH₂Cl₂) to give the desired N,N-dimethylformamidine (23 mg,32%). ¹H NMR (CDCl₃) δ1.67 (m, 1H), 2.03 (m, 2H), 2.24 (m, 1H), 2.70 (m,1H), 2.84 (m, 1H), 2.84 (s, 6H), 3.71 (s, 2H), 3.96 (d, 1H, J=15.0 Hz),4.07 (m, 1H), 4.15 (d, 1H, J=18.0 Hz), 4.36 (s, 2H), 7.16 (m, 5H), 7.31(s, 1H), 7.35 (d, 2H, J=7.8 Hz), 7.42 (d, 1H, J=7.8 Hz), 7.51 (br, 1H),7.64 (br, 1H), 8.68 (d, 1H, J=3.5 Hz).

[0308] Using General Procedure D: Conversion of the material from above(23 mg) to the hydrobromide salt provided AMD9777 (38 mg) as a whitesolid. ¹H NMR (D₂O) δ1.91 (br m, 1H), 2.26 (m, 2H), 2.45 (br m, 1H),2.97 (s, 3H), 3.03 (br m, 2H), 3.24 (s, 3H), 3.78 (d, 1H, J=12.9 Hz),3.85 (d, 1H, J=12.9 Hz), 4.04 (s, 2H), 4.45 (d, 1H, J=16.5 Hz), 4.63 (d,1H, J=16.5 Hz), 4.80 (m, 1H), 6.90 (d, 2H, J=8.1 Hz), 7.18 (d, 2H, J=7.8Hz), 7.52 (dd, 2H, J=3.0, 6.3 Hz), 7.59 (dd, 2H, J=3.0, 6.3 Hz), 7.64(s, 1H (NCHN)), 7.94 (t, 1H, J=6.9 Hz), 8.41 (d, 1H, J=7.8 Hz), 8.76 (d,1H, J=5.7 Hz); ¹³C NMR (D₂O) δ20.47, 20.92, 27.85, 36.27, 43.38, 49.66,50.21, 56.67, 63.21, 113.87 (2C), 126.09, 126.50 (2C), 127.63 (2C),130.61 (2C), 136.44 (2C), 139.65, 141.01, 148.27 (2C), 150.90, 151.94,156.35 (2C). ES-MS m/z 453 (M+H). Anal. Calcd. forC₂₈H₃₂N₆.3.3HBr.2.3H₂O: C, 44.29; H, 5.30; N, 11.07; Br, 34.46. Found:C, 44.36; H, 5.14; N, 10.74; Br, 34.44.

EXAMPLE: 28

[0309]

AMD9783: Preparation ofN-(4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-benzamidine(hydrobromide salt)

[0310] Preparation of S-benzylthiobenzimidate hydrobromide

[0311] To a solution of thiobenzamide (0.307 g, 2.24 mmol) in CH₂Cl₂ (11mL) was added benzyl bromide (0.26 mL, 2.19 mmol) and the resultantsolution was heated to reflux for 2 h. The mixture was cooled to roomtemperature and concentrated under reduced pressure. The resultantyellow solid was dried under vacuum to provide S-benzylthiobenzimidatehydrobromide (0.573 g, 85%). ¹H NMR (DMSO-d₆) δ4.76 (s, 2H), 7.34-7.44(m, 3H), 7.51-7.54 (m, 2H), 7.61-7.66 (m, 2H), 7.78-7.83 (m, 1H),7.88-7.91 (m, 2H), 11.92 (br s, 1H).

[0312] To a solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.130 g, 0.33 mmol) in ethanol (2 mL) was addedS-benzylthio-benzimidate hydrobromide (0.100 g, 0.33 mmol) and theresultant mixture was stirred at room temperature for 45 min. Themixture was treated with HBr saturated acetic acid (3 mL). Ether (50 mL)was added to precipitate a white solid that was allowed to settle to thebottom of the flask and the supernatant solution was decanted. The solidwas washed with ether (3×50 mL) and the remaining traces of ether wereremoved under reduced pressure. The solid was partitioned between NaOHsolution (10 N, 5 mL) and CH₂Cl₂ (20 mL). The phases were separated andthe aqueous phase was extracted with CH₂Cl₂ (4×10 mL). The combinedorganic extracts were dried (Na₂SO₄) and concentrated. Purification ofthe crude material by radial chromatography on silica gel (1 mm plate,20:1:1 CH₂Cl₂-CH₃OH-NH₄OH) provided 50 mg (32%) of the free base of thetitle compound as a white solid.

[0313] Using General Procedure D: Conversion of the free base (50 mg) tothe hydrobromide salt, followed by re-precipitation of the intermediatesolid from methanol/ether, gave AMD9783 (56 mg) as a white solid. ¹H NMR(D₂O) δ1.83-1.97 (m, 1H), 2.20-2.35 (m, 2H), 2.42-2.48 (m, 1H), 3.04 (brs, 2H), 3.79 (d, 1H, J=12.3 Hz), 3.87 (d, 1H, J=12.3 Hz), 4.21 (s, 2H),4.47 (d, 1H, J=16.5 Hz), 4.65 (d, 1H, J=16.5 Hz), 4.74-4.79 (m, 1H,overlaps with HOD), 7.02 (d, 2H, J=7.8 Hz), 7.22 (d, 2H, J=7.8 Hz), 7.29(dd, 2H, J=3.0, 6.0 Hz), 7.54 (dd, 2H, J=3.0, 6.0 Hz), 7.62-7.64 (m,4H), 7.74-7.78 (m, 1H), 7.91 (dd, 1H, J=6.3, 7.2 Hz), 8.39 (d, 1H, J=8.1Hz), 8.76 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ20.47, 20.93, 27.86, 45.43,50.31, 56.67, 63.26, 113.73, 126.07, 126.55, 127.64, 128.09, 128.89,129.83, 130.50, 130.67, 134.41, 136.54, 139.65, 140.99, 148.23, 150.92,151.93, 164.65; ES-MS m/z 501 (M+H). Anal. Calcd. for C₃₂H₃₂N₆.3.0HBr.2.4 H₂O: C, 48.86; H, 5.10; N, 10.68; Br, 30.47. Found: C, 48.97; H,4.89; N, 10.62; Br, 30.30.

EXAMPLE: 29

[0314]

AMD9784: Preparation ofN-(4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-acetamidine(hydrobromide salt)

[0315] Preparation of S-benzylthioacetimidate hydrobromide

[0316] To a solution of thioacetamide (0.478 g, 6.36 mmol) in CHCl₃ (16mL) was added benzyl bromide (0.76 mL, 6.39 mmol) and the resultantsolution was heated to reflux for 2 hours. The mixture was cooled toroom temperature. Ether (50 mL) was added and the mixture was cooled inan ice-water bath to precipitate a white solid. The supernatant solutionwas decanted and the solid was washed with ether (2×50 mL). The solidwas dried under vacuum to provide 1.44 g (92%) ofS-benzylthioacetimidate hydrobromide as a white solid. ¹H NMR (DMSO-d₆)δ2.63 (s, 3H), 4.61 (s, 2H), 7.34-7.46 (m, 5H), 11.89 (br s, 1H).

[0317] To a solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.154 g, 0.39 mmol) in ethanol (2 mL) was addedS-benzylthio-acetimidate hydrobromide (0.099 g, 0.40 mmol) and theresultant mixture was stirred at room temperature overnight. The mixturewas treated with HBr saturated acetic acid (3 mL). The mixture wasconcentrated under reduced pressure and the residue was partitionedbetween NaOH solution (10 N, 5 mL) and CH₂Cl₂ (10 mL). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×10 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by radial chromatography on silicagel (1 mm plate, 1:1:1 CH₃CN-CH₃OH-NH₄OH) provided 97 mg (57%) of thefree base of the title compound as a white solid.

[0318] Using General Procedure D: Conversion of the free base (97 mg) tothe hydrobromide salt, followed by re-precipitation of the intermediatesolid from methanol/ether, gave AMD9784 (113 mg) as a white solid. ¹HNMR (D₂O) δ1.83-1.98 (m, 1H), 2.17-2.33 (m, 5H), 2.41-2.47 (m, 1H),3.03-3.05 (m, 2H), 3.78 (d, 1H, J=12.3 Hz), 3.85 (d, 1H, J=12.3 Hz),3.96 (s, 2H), 4.46 (d, 1H, J=16.5 Hz), 4.64 (d, 1H, J=16.5 Hz),4.74-4.79 (m, 1H, overlaps with HOD), 6.91 (d, 2H, J=7.8 Hz), 7.18 (d,2H, J=7.8 Hz), 7.49-7.60 (m, 4H), 7.92 (dd, 1H, J=6.0, 7.8 Hz), 8.39 (d,1H, J=7.5 Hz), 8.75 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ18.91, 20.47,20.91, 27.86, 44.99, 50.26, 56.65, 63.18, 113.84, 126.08, 126.63,127.58, 130.52, 130.60, 134.29, 136.43, 139.64, 140.99, 148.25, 150.91,151.90, 164.99; ES-MS m/z 439 (M+H). Anal. Calcd. for C₂₇H₃₀N₆.3.1HBr.2.2 H₂O: C, 44.48; H, 5.18; N, 11.53; Br, 33.98. Found: C, 44.49; H,5.19; N, 11.25; Br, 34.13.

EXAMPLE: 30

[0319]

AMD9689: Preparation ofN-isobutyl-N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0320] Isobutyraldehyde (0.1 mL, 1.1 mmol) was condensed withN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(152 mg, 0.382 mmol) in dry CH₃OH (5 mL) for 17 h and the resultantimine was reduced with NaBH4 (81 mg, 2.14 mmol) for 1 h (see GeneralProcedures A and B). Purification of the crude product by radialchromatography (2 mm TLC plate, 50:1:1 CH₂Cl₂/CH₃OH/NH₄OH) gave the freeamine (43 mg, 25%).

[0321] Following General Procedure D: Conversion of the material fromabove (43 mg) to the hydrobromide salt gave AMD9689 (52 mg, 75%) as awhite solid. ¹H NMR (D₂O) δ0.88 (d, 6H, J=6.1 Hz), 1.82-1.96 (m, 2H),2.17-2.34 (m, 2H), 2.40-2.50 (m, 1H), 2.63 (d, 2H, J=7.6 Hz), 3.01-3.08(m, 2H), 3.65 (s, 2H), 3.81 (d, 1H, J=12.7 Hz), 3.88 (d, 1H, J=12.7 Hz),4.46 (d, 1H, J=16.6 Hz), 4.64 (d, 1H, J=16.1 Hz), 7.02 (d, 2H, J=7.9Hz), 7.23 (d, 2H, J=8.0 Hz), 7.51 (dd, 2H, J=6.2, 3.1 Hz), 7.59 (dd, 2H,J=6.0, 3.6 Hz), 7.94 (dd, 1H, J=8.1, 6.0 Hz), 8.41 (d, 1H, J=7.9 Hz),8.76 (d, 1H, J=5.7 Hz). ¹³C (D₂O) δ19.67 (2 carbons), 20.64, 21.12,25.95, 28.04, 50.35, 50.67, 54.46, 56.86, 63.38, 114.11 (2 carbons),126.30, 126.90 (2 carbons), 130.35 (2 carbons), 130.75, 130.93 (2carbons), 138.13, 139.87, 141.21, 148.46 (2 carbons), 151.03, 151.95.ES-MS m/z 454 (M+H) Anal Calc. for C₂₉H₃₅N₅.3.0HBr.1.9H₂O: C, 47.68; H,5.77; N, 9.59; Br, 32.81. Found: C, 47.53; H, 5.68; N, 9.46; Br, 32.94.

EXAMPLE: 31

[0322]

AMD9776: Preparation of(1H-Benzimidazol-2-ylmethyl)-(4-piperidin-2-yl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0323] Preparation of4-[(1-butyoxycarbonyl)-piperidin-2-yl]-benzaldehyde:

[0324] To a solution of 4-pyridin-2-yl-benzaldehyde (1.036 g, 5.65 mmol)in EtOH (95%, 3.1 mL) and conc. HCl (0.48 mL) in a Parr hydrogenationflask was added PtO₂ (57 mg, 0.251 mmol) and the mixture hydrogenated at50 psi H₂ for 40 h. The mixture was filtered through celite, the cakewashed with MeOH and the solvent was removed from the eluent underreduced pressure. The resultant yellow solid was dissolved in 1 N NaOH(30 mL) and extracted with ether (4×50 mL). The combined organic phaseswere dried (Na₂SO₄), filtered and concentrated under reduced pressure togive crude 1-(hydroxymethyl)-4-(piperidin-2-yl)-benzene (0.98 g) aswhite solid. To a solution of the solid in THF (25 mL), triethylamine(10 drops) and water (10 drops) was added di-tert-butyl dicarbonate(1.51 g, 6.92 mmol) and the reaction stirred at room temperature for 20h. The mixture was concentrated under reduced pressure and the residuetaken up in CH₂Cl₂ (100 mL) and washed with brine (3×75 mL). The organicphase was dried (Na₂SO₄), filtered and concentrated under reducedpressure to give crude1-(hydroxymethyl)-4-[(1-butoxycarbonyl)-piperidin-2-yl]-benzene (1.87 g)as an oil.

[0325] To a solution of the oil from above (1.87 g) in CH₂Cl₂ (100 mL)was added MnO₂ (85%, 5.90 g, 57.7 mmol) and the reaction stirred at roomtemperature for 18 h. The mixture was filtered through celite and thesolvent from the eluent was removed under reduced pressure. Purificationof the crude product (1.50 g) by flash chromatography (38 g silica, 99:1CH₂Cl₂: CH₃OH) gave the title compound (0.98 g, 60%). ¹H NMR (CDCl₃)δ1.25-1.69 (m, 13H), 1.95 (tt, 1H, J=13.4, 4.6 Hz), 2.31 (d, 1H, J=12.9Hz), 2.77 (td, 1H, J=12.4, 4.3 Hz), 4.09 (d, 1H, J=13.7 Hz), 5.44 (s,1H), 7.39 (d, 2H, J=7.7 Hz), 7.87 (d, 2H, J=8.2 Hz), 10.00 (s, 1H).

[0326] Following General Procedure B: To a solution of4-[(1-butyoxycarbonyl)-piperidin-2-yl]-benzaldehyde (189 mg, 0.651 mmol)and[1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(138 mg, 0.366 mmol) in CH₂Cl₂ (8 mL) was added NaBH(OAc)₃ (219 mg, 1.03mmol) and the reaction stirred overnight. Purification of the crude oilby column chromatography (12g silica, 40:1:1 CH₂Cl₂: CH₃OH: NH₄OH)followed by radial chromatography (1 mm TLC plate, 100:1:1 CH₂Cl₂:CH₃OH: NH₄OH) gave the desired free base (59 mg,29%).

[0327] Following General Procedure D: Conversion of the oil from above(59 mg) to the hydrobromide salt gave AMD9776 (59 mg, 75%). ¹H NMR (D₂O)δ1.07-1.22 (m, 1H), 1.24-1.40 (m, 1H), 1.43-1.68 (m, 2H), 1.81-1.98 (m,3H), 2.18-2.36 (m, 2H), 2.40-2.51 (m, 1H), 2.95-3.10 (m, 3H), 3.35 (d,1H, J=13.3 Hz), 3.75-3.92 (m, 3H), 4.48 (dd, 1H, J=16.7, 8.7 Hz), 4.66(dd, 1H, J=16.7, 5.7 Hz), 7.01 (d, 2H, J=7.5 Hz), 7.26 (dd, 2H, J=7.8,4.9 Hz), 7.48-7.54 (m, 2H), 7.55-7.61 (m, 2H), 7.91-7.97 (m, 1H), 8.41(d, 1H, J=8.3 Hz), 8.75-8.80 (m, 1H). ¹³C NMR (D₂O) δ20.48, 20.97,21.84, 22.29, 27.88, 29.86, 45.87, 50.32, 50.49, 56.61, 60.24, 63.27,63.37, 113.94 (2 carbons), 126.14, 126.71 (2 carbons), 127.06 (2carbons), 130.46, 131.03 (2 carbons), 136.85, 137.49, 139.71, 141.02,148.30 (2 carbons), 150.83, 151.88. ES-MS m/z 452 (M+H) Anal Calc. forC₂₉H₃₃N₅.3.0HBr.2.0H₂O: C, 47.69; H, 5.52; N, 9.59; Br, 32.82. Found: C,47.54; H, 5.42; N, 9.48; Br, 33.09.

EXAMPLE: 32

[0328]

AMD9713: Preparation of(1H-Benzimidazol-2-ylmethyl)-(4-piperidin-1-ylmethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0329] Using General Procedure A: To a stirred solution of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(AMD9882) (144 mg, 0.36 mmol) in dry MeOH (5 mL) was added piperidine(0.040 mL, 0.40 mmol) and sodium cyanoborohydride (44 mg, 0.70 mmol) andthe mixture stirred for 5 h. Purification of the crude product by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH, 50:1:1)afforded the desired adduct (50 mg, 30%) as a white foam.

[0330] Using General Procedure D: Conversion of the foam from above (25mg, 0.053 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD9713 (40 mg, 98%) asa yellow solid. ¹H NMR (D₂O) δ1.32-1.57 (m, 3H), 1.70-1.93 (m, 4H),2.22-2.31 (m, 2H), 2.44-2.48 (m, 1H), 2.65 (br t, 2H, J=11.4 Hz),3.01-3.03 (br m, 4H), 3.75 (s , 2H), 3.81 (d, 1H, J=12.6 Hz), 3.89 (d,1H, J=12.6 Hz), 4.48 (d, 1H, J=16.5 Hz), 4.67 (d, 1H, J=16.5 Hz),4.77-4.79 (m, 1H, overlap with HOD), 7.04 (d, 2H, J=7.8 Hz), 7.25 (d,2H, J=7.8 Hz), 7.51 (dd, 2H, J=6.3, 3 Hz), 7.59 (dd, 2H, J=6.3, 3 Hz),7.94 (dd, 1H, J=7.5, 6.3 Hz), 8.41 (d, 1H, J=8.1 Hz), 8.78 (d, 1H, J=5.4Hz); ¹³C NMR (D₂O) δ20.30, 20.82, 21.25, 22.91, 27.71, 50.19, 52.80,56.58, 59.44, 63.22, 113.70, 125.98, 126.62, 128.69, 130.29, 130.58,131.14, 138.14, 139.55, 140.92, 148.17, 150.66, 151.68. ES-MS m/z 466(M+H). Anal. Calcd. for C₃₀H₃₅N₅.3.2HBr.1.5H₂O: C, 47.94; H, 5.53; N,9.32; Br, 34.02. Found: C, 47.72; H, 5.54; N, 9.22; Br, 34.32.

EXAMPLE: 33

[0331]

AMD9722: Preparation of(1H-Benzimidazol-2-ylmethyl)-(4-methylaminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0332] Using General Procedure B: To a solution of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(AMD9882) (120 mg, 0.30 mmol) in MeOH (2 mL) was added methylamine (2.0M solution in methanol, 1 mL, 2.00 mmol) and the resultant solution wasstirred at room temperature for 5 hours. Solid NaBH₄ (18 mg, 0.48 mmol)was added to the solution and the mixture was stirred at roomtemperature for an additional 30 minutes. Purification of the crudematerial by radial chromatography on silica gel (1 mm plate, 50:1:1CH₂Cl₂/CH₃OH/NH₄OH) provided the free base of the title compound (74 mg,59%) as a white solid.

[0333] Using General Procedure D: Conversion of the free base (74 mg) tothe hydrobromide salt, followed by re-precipitation of the intermediatesolid from methanol/ether, gave AMD9722 (111 mg) as a white solid. ¹HNMR (D₂O) δ1.84-1.97 (m, 1H), 2.21-2.47 (m, 6H), 3.04 (br s, 2H), 3.66(s, 2H), 3.81 (d, 1H, J=12.6 Hz), 3.88 (d, 1H, J=12.6 Hz), 4.46 (d, 1H,J=16.5 Hz), 4.64 (d, 1H, J=16.5 Hz), 4.77-4.79 (m, 1H), overlaps withHOD), 7.01 (d, 2H, J=8.1 Hz), 7.24 (d, 2H, J=8.1 Hz), 7.49-7.53 (m, 2H),7.56-7.60 (m, 2H), 7.93 (dd, 1H, J=6.0, 7.5 Hz), 8.40 (d, 1H, J=8.1 Hz),8.7 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ18.71, 19.20, 26.11, 30.37, 48.50,49.69, 54.93, 61.49, 112.19, 124.37, 124.95, 128.27, 128.77, 128.84,129.07, 136.21, 137.94, 139.28, 146.54, 149.08, 150.08; ES-MS m/z 412(M+H). Anal. Calcd. for C₂₆H₂₉N₅.3.0 HBr.2.0 H₂O: C, 45.24; H, 5.26; N,10.15; Br, 34.73. Found: C, 45.13; H, 5.20; N, 10.02; Br, 34.81.

EXAMPLE: 34

[0334]

AMD9724: Preparation of(1H-Benzimidazol-2-ylmethyl)-(4-piperazin-1-ylmethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0335] Preparation of 2,2,2-trifluoro-1-piperazin-1-yl-ethanone (Xu, D.;Repic, O.; Blacklock, J. Tetrahedron Lett. 1995, 41, 7357-7360):

[0336] To a solution of piperazine (1.444 g, 16.8 mmol) in MeOH (10 mL)was added trifluroacetic acid ethyl ester (2.0 mL, 16.8 mmol) and themixture stirred at room temperature overnight. The reaction wasconcentrated and purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 9:1) to afford the desired mono-protected piperazineadduct (1.77 g, 58%) as a pale yellow oil. ¹H NMR (CDCl₃) δ1.70 (br s,1H), 2.90-2.94 (m, 4H), 3.56-3.59 (m, 2H), 3.64-3.67 (m, 2H).

[0337] Using General Procedure A: To a stirred solution of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(AMD9882) (262 mg, 0.66 mmol) in dry MeOH (10 mL) was added2,2,2-trifluoro-1-piperazin-1-yl-ethanone (172 mg, 0.95 mmol) and sodiumcyanoborohydride (54 mg, 0.86 mmol) and the mixture stirred overnight.Purification of the crude product by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 100:1:1) followed by radial chromatography on silicagel (2 mm plate, CH₂Cl₂/MeOH/NH₄OH, 50:1:1) afforded the desired adduct(68 mg, 18%) as a white foam.

[0338] To a solution of the TFA-protected adduct from above (68 mg, 0.12mmol) in MeOH (3 mL) was added powdered K₂CO₃ (55 mg, 0.40 mmol) and themixture stirred at reflux for 1.5 h and at room temperature overnight.The reaction was diluted with CH₂Cl₂ (30 mL) and water (20 mL), thephases separated and the aqueous layer extracted with CH₂Cl₂ (2×15 mL).The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the crude product by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH, 100:1:1then 50:1:1) afforded the desired adduct (54 mg, 97%) as a clear oil.

[0339] Using General Procedure D: Conversion of the foam from above (23mg, 0.049 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD9724 (35 mg, 85%) asa white solid. ¹H NMR (D₂O) δ1.89-1.93 (m, 1H), 2.21-2.33 (m, 2H),2.42-2.48 (m, 1H), 3.03-3.05 (m, 2H), 3.24-3.28 (m, 4H), 3.42-3.44 (m,4H), 3.82 (d, 1H, J=12.9 Hz), 3.87 (s , 2H), 3.90 (d, 1H, J=12.6 Hz),4.46 (d, 1H, J=16.5 Hz), 4.65 (d, 1H, J=16.5 Hz), 4.77-4.79 (m, 1H,overlap with HOD), 7.07 (d, 2H, J=7.8 Hz), 7.27 (d, 2H, J=7.8 Hz), 7.51(dd, 2H, J=6, 3 Hz), 7.59 (dd, 2H, J=6, 3 Hz), 7.94 (dd, 1H, J=7.2, 6.6Hz), 8.41 (d, 1H, J=8.1 Hz), 8.78 (d, 1H, J=6.2 Hz); ¹³C NMR (D₂O )δ20.45, 20.97, 27.87, 41.14, 48.19, 50.17, 56.75, 59.92, 63.27, 113.97,126.15, 126.68, 128.00, 130.53, 130.94, 131.34, 138.82, 139.74, 141.09,148.33, 150.78, 151.81. ES-MS m/z 467 (M+H). Anal. Calcd. forC₂₉H₃₄N₆.4HBr.2.5H₂O: C, 41.70; H, 5.19; N, 10.06; Br, 38.26. Found: C,41.72; H, 5.16; N, 9.82; Br, 38.41.

EXAMPLE: 35

[0340]

AMD9733: Preparation of[4-(4-Allyl-piperazin-1-ylmethyl)-benzyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0341] Preparation of 1-allyl-piperazine

[0342] To a stirred solution of2,2,2-trifluoro-1-piperazin-1-yl-ethanone (515 mg, 2.83 mmol) in dryCH₃CN (6 mL) was added allyl bromide (0.32 mL, 3.7 mmol) and powderedpotassium carbonate (0.78 g, 5.65 mmol) and the mixture stirredovernight. The reaction was concentrated under reduced pressure, dilutedwith CH₂Cl₂ (30 mL) and water (30 mL) and the aqueous layer extractedwith CH₂Cl₂ (2×20 mL). The combined organic extracts were dried(Na₂SO₄), filtered and concentrated in vacuo to afford the crudedi-protected piperazine (0.554 g) which was used without furtherpurification in the next reaction.

[0343] To a solution of the TFA-protected piperazine from above (0.554g) in MeOH (10 mL) was added powdered K₂CO₃ (0.689 g, 5.0 mmol) and themixture stirred at reflux for 1.5 h and at room temperature overnight.The reaction was diluted with CH₂Cl₂ (30 mL) and water (20 mL), thephases separated and the aqueous layer extracted with CH₂Cl₂ (2×15 mL).The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo to afford the title compound (0.132 g, 42%) as apale yellow oil. ¹H NMR (CDCl₃) δ1.96 (br s, 1H), 2.39-2.44 (br m, 4H),2.89-2.92 (m, 4H), 2.98 (d, 2H, J=6 Hz), 5.13-5.21 (m, 2H), 5.79-5.93(m, 1H).

[0344] Using General Procedure B: To a stirred solution of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(AMD9882) (262 mg, 0.66 mmol) and 1-allyl-piperazine (132 mg, 1.05 mmol)in CH₂Cl₂ (6 mL) was added NaBH(OAc)₃ (184 mg, 0.87 mmol) and theresultant mixture was stirred at room temperature for 2 h. Purificationof the crude material by column chromatography on silica gel gel(CH₂Cl₂/MeOH/NH₄OH, 95:4:1) afforded the desired adduct (267 mg) as aclear oil.

[0345] Using General Procedure D: Conversion of the oil from above (233mg) to the hydrobromide salt followed by re-precipitation of theintermediate solid from methanol/ether gave AMD9733 (335 mg, 56% over 2steps) as a yellow solid. ¹H NMR (D₂O) δ1.89-1.94 (m, 1H), 2.21-2.33 (m,2H), 2.42-2.46 (m, 1H), 3.03-3.05 (m, 2H), 3.30-3.34 (m, 4H), 3.44-3.51(m, 4H), 3.80-3.90 (m, 6H), 4.47 (d, 1H, J=16.5 Hz), 4.65 (d, 1H, J=16.5Hz), 4.77-4.79 (m, 1H, overlap with HOD), 5.62 (d, 1H, J=17.1 Hz), 5.64(d, 1H, J=9.6 Hz), 5.81-5.91 (m, 1H), 7.07 (d, 2H, J=7.8 Hz), 7.28 (d,2H, J=7.8 Hz), 7.50 (dd, 2H, J=6,3 Hz), 7.59 (dd, 2H, J=6,3 Hz), 7.95(dd, 1H, J=7.8, 6 Hz), 8.42 (d, 1H, J=7.8 Hz), 8.78 (d, 1H, J=5.5 Hz);¹³C NMR (D₂O) δ20.72, 21.26, 28.15, 48.52, 48.64, 50.48, 56.99, 59.47,59.73, 63.48, 114.29, 125.18, 126.44, 126.97, 127.79, 128.76, 130.70,131.28, 131.71, 139.20, 140.03, 141.33, 148.62, 150.97, 152.01. ES-MSm/z 507 (M+H). Anal. Calcd. for C₃₂H₃₈N₆.3.9HBr.2.7H₂O.0.4C₄H₁₀O: C,44.81; H, 5.74; N, 9.33; Br, 34.60. Found: C, 44.62; H, 5.49; N, 9.26;Br, 34.84.

EXAMPLE: 36

[0346]

AMD9734: Preparation of(1H-Benzimidazol-2-ylmethyl)-(4-dimethylaminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0347] Using General Procedure B: Reaction of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(AMD9882) (157 mg, 0.40 mmol) and dimethylamine (2.0 M in THF, 0.4 mL,0.80 mmol) with NaBH(OAc)₃ (0.179 g, 0.84 mmol) in CH₂Cl₂ (4 mL)overnight followed by purification of the crude material by radialchromatography on silica gel (2 mm plate, 50:1:1 CH₂Cl₂—CH₃OH-NH₄OH)provided the free base of the title compound (72 mg, 43%) as a colorlessoil.

[0348] Using General Procedure D: Conversion of the free base (72 mg) tothe hydrobromide salt, followed by re-precipitation of the intermediatesolid from methanol/ether, gave AMD9734 (77 mg) as a white solid. ¹H NMR(D₂O ) δ1.86-1.98 (m, 1H), 2.20-2.48 (m, 9H), 3.05 (br s, 2H), 3.80 (s,2H), 3.81 (d, 1H, J=12.6 Hz), 3.90 (d, 1H, J=12.6 Hz), 4.50 (d, 1H,J=16.5 Hz), 4.68 (d, 1H, J=16.5 Hz), 4.78-4.83 (m, 1H, overlaps withHOD), 7.06 (d, 2H, J=7.8 Hz), 7.28 (d, 2H, J=7.8 Hz), 7.48-7.52 (m, 2H),7.57-7.61 (m, 2H), 7.95 (dd, 1H, J=6.0, 7.5 Hz), 8.42 (d, 1H, J=7.8 Hz),8.79 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ20.47, 21.03, 27.90, 42.16,50.41, 56.77, 60.12, 63.45, 113.98, 126.18, 126.85, 129.16, 130.43,130.91, 131.12, 138.45, 139.74, 141.11, 148.37, 150.77, 151.99; ES-MSm/z 426 (M+H). Anal. Calcd. for C₂₇H₃₁N₅.3.2 HBr.2.2 H₂O: C, 44.78; H,5.37; N, 9.67; Br, 35.31. Found: C, 44.76; H, 5.27; N, 9.52; Br, 35.29.

EXAMPLE: 37

[0349]

AMD 9775: Preparation of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-[4-(1,2,4-triazol-4-yliminomethyl)-benzyl]-amine(hydrobromide salt)

[0350] Using General Procedure B: Reaction of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(AMD9882) (206 mg, 0.52 mmol) and 4-amino-1,2,4-triazole (70 mg, 0.82mmol) with NaBH(OAc)₃ (0.223 g, 1.05 mmol) in CH₂Cl₂ (4 mL) and aceticacid (0.12 mL) overnight followed by purification of the crude materialby radial chromatography on silica gel (2 mm plate, 100:1:1CH₂Cl₂—CH₃OH—NH₄OH) provided 87 mg (36%) of the free base of the titlecompound as a colorless oil.

[0351] Using General Procedure D: Conversion of the free base (87 mg) tothe hydrobromide salt, followed by re-precipitation of the intermediatesolid from methanol/ether, gave AMD9775 (83 mg) as a white solid. ¹H NMR(D₂O) δ1.85-1.99 (m, 1H), 2.20-2.34 (m, 2H), 2.45-2.49 (m, 1H), 3.06 (s,2H), 3.82 (d, 1H, J=12.6 Hz), 3.91 (d, 1H, J=12.6 Hz), 4.46 (d, 1H,J=16.5 Hz), 4.65 (d, 1H, J=16.5 Hz), 4.79-4.83 (m, 1H, overlaps withHOD), 7.27-7.32 (m, 2H), 7.36-7.44 (m, 4H), 7.50-7.56 (m, 2H), 7.95 (dd,1H, J=6.3, 7.5 Hz), 8.41-8.43 (m, 2H), 8.79 (d, 1H, J=5.4 Hz), 9.07 (brs, 2H); ¹³C NMR (D₂O) δ20.44, 21.04, 27.86, 50.24, 56.96, 63.44, 113.90,113.97, 126.21, 126.53, 126.82, 129.02, 129.99, 130.44, 130.69, 130.84,135.15, 139.77, 141.11, 141.88, 144.07, 148.36, 150.67, 151.27, 151.54,160.78, 195.56; ES-MS m/z 463 (M+H). Anal. Calcd. for C₂₇H₂₆N₈.3.0HBr.1.8 H₂O: C, 43.96; H, 4.45; N, 15.19; Br, 32.49. Found: C, 43.99; H,4.40; N, 14.83; Br, 32.61.

EXAMPLE: 38

[0352]

AMD9671: Preparation ofN′-(4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-ethane-1,2-diamine(hydrobromide salt)

[0353] Using General Procedure B: To a stirred solution ofN′-(1H-benzirnidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(250 mg, 0.629 mmol) and (2-oxo-ethyl)-carbamic acid tert-butyl ester(100 mg, 0.628 mmol) in THF (6.3 mL) was added NaBH(OAc)₃ (173 mg, 0.816mmol) and the mixture was stirred at room temperature for 22 h.Purification of the crude material by column chromatography on silicagel (200:5:1 CH₂Cl₂/MeOH/NH₄OH) afforded a colourless oil (47 mg).

[0354] Using General Procedure D: Conversion of the oil from above (47mg, 0.11 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD9671 (72 mg, 14%) asa colourless solid. ¹H NMR (D₂O) δ1.88 (m, 1H), 2.24 (m, 2H), 2.42 (m,1H), 3.01 (m, 2H), 3.25 (m, 4H), 3.73 (m, 2H), 3.82 (dd, 2H, J=19, 12Hz), 4.40 (d, 1H, J=16 Hz), 4.59 (d, 1H, J=16 Hz), 4.75 (m, 1H), 7.03(d, 2H, J=7.8 Hz), 7.23(d, 2H, J=7.8 Hz), 7.48 (m, 2H), 7.55 (m, 2H),7.88 (dd, 1H, J=7.8, 6.0 Hz), 8.35 (d, 1H, J=7.8 Hz), 8.73 (d, 1H, J=5.7Hz); ¹³C NMR (D₂O) δ20.46, 20.91, 27.85, 35.73, 43.93, 50.12, 50.82,56.63, 63.00, 114.01, 126.02, 126.50, 130.05, 130.86, 138.33, 139.77,140.88, 148.06, 150.92, 151.74. ES-MS m/z 441 (M+H). Anal. Calcd. forC₂₇H₃₂N₆.3.9HBr.2.5H₂O: C, 40.48; H, 5.15; N, 10.49; Br, 38.90. Found:C, 40.35; H, 4.96; N, 10.25; Br, 39.04.

EXAMPLE: 39

[0355]

AMD9701: Preparation of(1H-benzimidazol-2-ylmethyl)-(4-butylaminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0356] A solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(165 mg, 0.415 mmol) and butyraldehyde (50 mg, 0.69 mmol) in MeOH (4 mL)was heated at reflux for 30 minutes. The solution was allowed to cool toroom temperature, 10% Pd/C (20 mg, 0.019 mmol) was added, and themixture was stirred under hydrogen atmosphere (1 atm) at roomtemperature for 20 h. The mixture was filtered through Celite and thesolvent from the filtrate was removed under reduced pressure.Purification of the crude material by column chromatography on silicagel (200:5:1 CH₂Cl₂/MeOH/NH₄OH) afforded AMD9701 (16 mg, 8%) as acolourless foam. ¹H NMR (CDCl₃) δ0.87 (m, 3H), 1.24-1.49 (m, 4H), 1.68(m, 1H), 2.02 (m, 2H), 2.26 (m, 1H), 2.56 (m, 2H), 2.79 (m, 2H), 3.68(s, 2H), 3.73 (s, 2H), 3.97 (d, 1H, J=17 Hz), 4.08 (m, 1H), 4.17 (d, 1H,J=17 Hz), 7.18 (m, 5H), 7.35 (m, 2H), 7.42 (m, 1H), 7.58 (m, 2H), 8.69(d, 1H, J=3.9 Hz); ^(—)C NMR (CDCl₃) δ14.39, 20.84, 21.79, 23.77, 29.63,32.57, 48.88, 49.53, 54.11, 60.58, 111.30, 119.11, 121.68, 122.04,122.60, 128.47, 128.99, 135.09, 137.55, 138.30, 139.82, 147.33, 156.73,157.89. ES-MS m/z 454 (M+H). Anal. Calcd. for C₂₉H₃₅N₅.1.3H₂O: C, 73.02;H, 7.94; N, 14.68. Found: C, 73.06; H, 7.70; N, 14.32.

EXAMPLE: 40

[0357]

AMD9725: Preparation of(1H-benzimidazol-2-ylmethyl)-(4-diallylaminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0358] To a solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(156 mg, 0.39 mmol) in CH₂Cl₂ (4 mL) was added N,N-diisopropylethylamine(65 μL, 0.37 mmol). Allyl bromide (35 μL, 0.40 mmol) was added dropwiseand the resultant mixture stirred at room temperature for 3 days. Thereaction mixture was diluted with CH₂Cl₂ (50 mL) and washedconsecutively with H₂O (2×5 mL), saturated aqueous NaHCO₃ (5 mL) andsaturated aqueous NaCl (5 mL). The aqueous layer was extracted withCH₂Cl₂ (20 mL) and the combined organic extracts were dried (MgSO₄) andconcentrated under reduced pressure to afford a light yellow foam (100mg). Purification by column chromatography on silica gel (200:1:1followed by 100:1:1—CH₂Cl₂:MeOH:NH₄OH) followed by radial chromatographyon silica gel (1000:1:1—EtOAc:MeOH:NH₄OH) afforded AMD9725 (24.5 mg,14%) as a light yellow foam. ¹H NMR (CDCl₃) δ1.62-1.75 (m, 1H),1.97-2.08 (m, 2H), 2.22-2.30 (m, 1H), 2.66-2.77 (m, 1H), 2.77-2.92 (m,1H), 3.01 (d, 4H, J=6.3 Hz), 3.48 (s, 2H), 3.74 (s, 2H), 3.99 (d, 1H,J=16.8 Hz), 4.07-4.12 (m, 1H), 4.18 (d, 1H, J=16.8 Hz), 5.09-5.17 (m,4H), 5.83 (ddt, 2H, J=16.8, 10.2, 6.3 Hz), 7.15-7.20 (m, 5H), 7.34 (d,2H, J=7.8 Hz), 7.41 (d, 1H, J=7.8 Hz), 7.48-7.56 (m, 1H), 7.60-7.69 (m,1H), 8.69 (d, 1H, J=4.2 Hz); ¹³C NMR (CDCl₃) δ19.69 21.65, 27.53, 46.90,52.08, 54.63, 55.44, 58.47, 109.24, 115.61, 117.04, 119.79, 120.49,126.67, 127.13, 132.99, 134.17, 135.45, 136.13, 136.56, 145.22, 154.64,155.80. ES-MS m/z 478.4 (M+H). Anal. Calcd. for C₃₁H₃₅N₅.0.5H2O: C,76.51; H, 7.46; N, 14.39. Found: C, 76.67; H, 7.45; N, 14.18.

EXAMPLE: 41

[0359]

AMD9726: Preparation of(4-allylaminomethyl-benzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0360] To a solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(200 mg, 0.39 mmol) in CH₂Cl₂ (˜0.4 mL) was addedN,N-diisopropylethylamine (90 μL, 0.52 mmol). Allyl bromide (35 μL, 0.40mmol) was dissolved in CH₂Cl₂ (˜9.6 mL) and added to the amine mixtureat a rate of 5.5 mL/hour. The resultant mixture was stirred at roomtemperature for 24 hours. The reaction mixture was diluted with CH₂Cl₂(50 mL) and washed consecutively with H₂O (5 mL), saturated aqueousNaHCO₃ (5 mL) and saturated aqueous NaCl (5 mL). The aqueous layer wasextracted with CH₂Cl₂ (20 mL) and the combined organic extracts weredried (MgSO₄) and concentrated under reduced pressure. Purification bycolumn chromatography on silica gel (200:1:1 followed by100:1:1—EtOAc:MeOH:NH₄OH) followed by radial chromatography on silicagel (250:1:1—EtOAc:MeOH:NH₄OH) afforded AMD9725 (36 mg, 21%) as a lightyellow foam. ¹H NMR (CDCl₃) δ1.56-1.75 (m, 1H), 1.97-2.08 (m, 2H),2.24-2.31 (m, 1H), 2.65-2.77 (m, 1H), 2.77-2.91 (m, 1H), 3.21 (d, 2H,J=5.7 Hz), 3.69 (s, 2H), 3.73 (s, 2H), 3.97 (d, 1H, J=16.8 Hz),4.04-4.16 (m, 1H), 4.17 (d, 1H, J=16.8 Hz), 5.07 (d, 1H, J=9.9 Hz), 5.15(dd, 1H, J=17.1, 1.2 Hz), 5.88 (ddt, 1H, J=17.1, 10.5, 6.0 Hz),7.10-7.19 (m, 5H), 7.35 (d, 2H, J=7.8 Hz), 7.42 (d, 1H, J=7.5 Hz),7.45-7.57 (m, 1H), 7.58-7.68 (m, 1H), 8.69 (d, 1H, J 4.2 Hz); ¹³C NMR(CDCl₃) δ20.83, 22.89, 28.67, 47.95, 51.11, 52.33, 53.17, 59.68, 110.37,115.39, 118.11, 120.91, 121.66, 127.59, 128.07, 134.13, 136.17, 136.60,137.48, 138.56, 146.38, 155.80, 156.94. ES-MS m/z 438.3 (M+H). Anal.Calcd. for C₂₈H₃₁N₅.0.8H₂O: C, 74.40; H, 7.27; N, 15.49. Found: C,74.36; H, 7.25; N, 15.31.

EXAMPLE: 42

[0361]

AMD9754: Preparation of(1H-benzimidazol-2-ylmethyl)-(4-pyrrolidin-1-ylmethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0362] Using General Procedure B: To a stirred solution of4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(150 mg, 0.37 mmol), pyrrolidine (30 μL, 0.36 mmol) and AcOH (20 μL,0.37 mmol) in THF (4 mL) was added NaBH(OAc)₃ (235 mg, 1.11 mmol) andthe mixture was stirred at room temperature for 1.5 hours. Purificationof the crude white foam (205 mg) by column chromatography on silica gel(100:1:1—CH₂Cl₂:MeOH:NH₄OH) afforded the desired product (160 mg, 96%)as a white foam.

[0363] Using General Procedure D: Conversion of the foam from above tothe hydrobromide salt afforded AMD9754 as a white solid. ¹H NMR (CD₃OD)δ1.82-1.98 (m, 3H), 1.98-2.15 (m, 2H), 2.18-2.36 (m, 2H), 2.42-2.53 (m,1H), 2.85-2.97 (m, 2H), 3.03-3.14 (m, 4H), 3.85 (d, 1H, J=12.9 Hz), 3.94(d, 1H, J=12.9 Hz), 4.07 (s, 2H), 4.45 (d, 1H, J=16.5 Hz), 4.66 (d, 1H,J=16.2 Hz), 4.74-4.79 (m, 1H), 7.27 (d, 2H, J=7.8 Hz), 7.55 (dd, 2H,J=6.3, 3.3 Hz), 7.63 (d, 2H, J=7.8 Hz), 7.77 (dd, 2H, J=6.3, 3.3 Hz),7.97 (dd, 1H, J=7.8, 6.0 Hz), 8.42 (d, 1H, J=8.1 Hz), 9.01 (d, 1H, J=5.4Hz); ¹³C NMR (D₂O) δ20.47, 21.05, 22.81, 27.90, 50.46, 53.75, 56.76,57.26, 63.49, 113.98, 126.18, 126.74, 130.31, 130.42, 130.62, 130.94,138.04, 139.76, 141.10, 148.36, 150.77, 152.06. ES-MS m/z 452.3 (M+H).Anal. Calcd. for C₂₉H₃₃N₅.3.0HBr.2.1H₂O: C, 47.57; H, 5.53; N, 9.57; Br,32.74. Found: C, 47.69; H, 5.53; N, 9.48; Br, 32.48.

EXAMPLE: 43

[0364]

AMD9723: Preparation of(1H-Benzimidazol-2-ylmethyl)-(4-morpholin-4-ylmethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0365] Using General Procedure A: To a stirred solution of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(0.285 g, 0.72 mmol) in dry MeOH (5 mL) was added morpholine (0.068 mL,0.78 mmol) and sodium cyanoborohydride (0.107 g, 1.7 mmol) and themixture stirred at room temperature for 24 h. Purification of the crudeproduct by radial chromatography on a 2 mm TLC grade silica gel plate(CH₂Cl₂/MeOH/NH₄OH, 100:1:1) afforded the desired product (23 mg, 7%) asa colourless oil.

[0366] Using General Procedure D: Conversion of the oil from above (23mg, 0.049 mmol) to the hydrobromide salt gave AMD9723 as a white solid(36 mg). ¹H NMR (D₂O) δ1.79-2.03 (br m, 1H), 2.14-2.38 (br m, 2H),2.38-2.54 (br m, 1H), 2.83-3.15 (m, 6H), 3.51-3.71 (m, 2H), 3.76-4.10(m, 6H), 4.48 (d, 1H, J=16.5 Hz), 4.66 (d, 1H, J=16.8 Hz), 7.07 (d, 2H,J=7.8 Hz), 7.27 (d, 2H, J=7.5 Hz), 7.12-7.68 (m, 4H), 7.94 (t, 1H, J=6.3Hz), 8.41 (d, 1H, J=7.8 Hz), 8.78 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O)δ20.45, 20.99 27.87, 50.33, 51.31 (2 carbons), 56.75, 59.89, 63.39,63.98 (2 carbons), 113.92 (2 carbons), 126.13, 126.66 (2 carbons),127.83, 130.56, 130.84 (2 carbons), 131.47 (2 carbons), 138.67, 139.75,141.07, 148.27, 150.81, 151.94; ES-MS m/z 468 (M+H); Anal. Calcd. forC₂₉H₃₃N₅O.3.0HBr.2.0H₂O: C, 46.67; H, 5.40; N, 9.38; Br, 32.12. Found:C, 46.71; H, 5.34; N, 9.22; Br, 32.17.

EXAMPLE: 44

[0367]

AMD9698: Preparation of(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(4-thiomorpholin-4-ylmethyl-benzyl)-amine.

[0368] Following the General Procedure A:4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde(200 mg, 0.50 mmol) and thiomorpholine (51 μL, 0.50 mmol) were convertedinto the corresponding reductive amination product using the followingquantities of reagents and solvents: sodium cyanoborohydride (63 mg, 1.0mmol), MeOH (3 mL). The reaction time in this case was 5 h. Purificationof the crude material thus obtained by radial chromatography (silicagel, 1 mm plate, 50:2:1 CH₂Cl₂-MeOH-NH₄OH) afforded 63 mg (26%) ofAMD9698 as a white foam. ¹H NMR (CDCl₃) δ1.67-1.72 (m, 1H), 2.02-2.09(m, 2H), 2.25-2.27 (m, 1H), 2.62 (s, 8H), 2.68-2.73 (m, 1H), 2.80-2.85(m, 1H), 3.40 (s, 2H), 3.74 (s, 2H), 3.98 (d, 1H, J=16 Hz), 4.10 (dd,1H, J=9, 6 Hz), 4.19 (d, 1HI, J=16 Hz), 7.14-7.20 (m, 5H), 7.35 (d, 2H,J=8 Hz), 7.42 (dd, 1H, J=8, 1 Hz), 7.53-7.63 (m, 2H), 8.70 (dd, 1H, J=5,1 Hz); ¹³C NMR (CDCl₃) δ21.3, 23.4, 27.9, 29.1, 48.5, 53.6, 54.8, 60.2,63.3, 110.8, 118.6, 121.3, 122.2, 128.3, 128.9, 134.6, 136.9, 137.1,138.1, 146.9, 156.3, 157.4. ES-MS m/z 484 (M+H). Anal. Calcd. forC₂₉H₃₃N₅S.0.1CH₂Cl₂.0.3H₂O: C, 70.25; H, 6.85; N, 14.08; S, 6.44. Found:C, 70.42; H, 6.90; N, 13.70; S, 6.29.

EXAMPLE: 45

[0369]

AMD 11173: Preparation of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(2-cyclopropylaminomethyl-benzyl)-amine(HBr salt).

[0370] Using general procedure B {direct reductive animation usingNaBH(OAc)₃}: Reaction of phthalic dicarboxaldehyde (0.960 g, 7.16 mmol)and(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.991 g, 3.58 mmol) with NaBH(OAc)₃ (3.24 g, 15.3 mmol) in CH₂Cl₂ (20mL) for 65 hours, followed by stirring in THF (10 mL) and 4 N HCl (20mL) provided a crude product. Purification of the crude material bycolumn chromatography on silica gel (37 g silica, 30:1 CH₂Cl₂: CH₃OH)provided 1.21 g (45%) of mixture of benzylic aldehyde and benzylicalcohol products.

[0371] This mixture of aldehyde and alcohol (1.21 g, 3.04 mmol) wasdissolved in CH₂Cl₂ (20 mL), treated with MnO₂ (1.990 g, 19.5 mmol) andstirred for 48 hours. The suspension was filtered through celite andconcentrated to give the crude product. Purification by columnchromatography on silica gel (51 g silica, 60:1 CH₂Cl₂: CH₃OH) provided942 mg (66% over three steps) of o-benzylic aldehyde intermediate as ayellow foam.

[0372] The aldehyde from above (0.119 g, 0.300 mmol) was stirred withcyclopropyl amine (32 μL, 0.461 mmol) in CH₃OH (2.5 mL) for 1 hour, thentreated with NaBH₄ (18 mg, 0.475 mmol). The mixture was concentratedafter 1 hour. The residue was diluted with CH₂Cl₂ (20 mL) and washedwith brine (3×10 mL). The combined aqueous phase was extracted withCH₂Cl₂ (1×15 mL). The combined organic phases were dried (Na₂SO₄),filtered and concentrated to give the crude product. Purification byradial chromatography on silica gel (1 mm plate, 100:1:1 CH₂Cl₂: CH₃OH:NH₄OH) provided 0.066 g (50%) of a white foam.

[0373] Using General Procedure D: Conversion of the foam from above (66mg, 0.151 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD11173 (100 mg, 92%)as a white solid. ¹H NMR (D₂O) δ0.63-0.79 (m, 4H), 1.83-1.98 (m, 1H),2.18-2.30 (m, 1H), 2.31-2.41 (m, 1H), 2.43-2.58 (m, 2H), 2.98-3.13 (m,2H), 3.92 (d, 1H, J=13.7 Hz), 4.14 (d, 1H, J=13.2 Hz), 4.24 (d, 1H,J=13.6 Hz), 4.41 (d, 1H, J=16.6 Hz), 4.48 (d, 1H, J=13.1 Hz), 4.59 (d,1H, J=16.4 Hz), 6.92 (t, 1H, J=7.5 Hz), 7.00 (d, 1H, J=7.4 Hz), 7.19 (t,1H, J=7.0 Hz), 7.41 (d, 1H, J=7.4 Hz), 7.51-7.56 (m, 2H), 7.58-7.63 (m,2H), 7.91 (dd, 1H, J=7.7, 6.1 Hz), 8.40 (d, 1H, J=7.9 Hz), 8.74 (d, 1H,J=5.22); ¹³C NMR (D₂O) 6 3.53, 20.43, 20.93, 27.92, 30.04, 48.44, 49.35,53.22, 62.29, 113.95, 126.24, 126.91, 129.42, 129.54, 130.32, 130.60,131.16, 132.17, 135.58, 139.96, 141.16, 148.33, 150.52, 150.89. ES-MSm/z 438 (M+H). Anal. Calcd. for C₂₈H₃₁N₅.3.0HBr.2.3H₂O: C, 46.71; H,5.38; N, 5.38; N, 9.73; Br, 33.30. Found: C, 46.72; H, 5.36; N, 9.59;Br, 33.21.

EXAMPLE: 46

[0374]

AMD 11173: Preparation of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(2-allylaminomethyl-benzyl)-amine(HBr salt).

[0375] Using general procedure B {direct reductive amination usingNaBH(OAc)₃}: Reaction of phthalic dicarboxaldehyde (0.960 g, 7.16 mmol)and(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.991 g, 3.58 mmol) with NaBH(OAc)₃ (3.24 g, 15.3 mmol) in CH₂Cl₂ (20mL) for 65 hours, followed by stirring in THF (10 mL) and 4 N HCl (20mL) provided a crude product. Purification of the crude material bycolumn chromatography on silica gel (37 g silica, 30:1 CH₂Cl₂: CH₃OH)provided 1.21 g (45%) of mixture of benzylic aldehyde and benzylicalcohol products. This mixture of aldehyde and alcohol (1.21 g, 3.04mmol) was dissolved in CH₂Cl₂ (20 mL), treated with MnO₂ (1.990 g, 19.5mmol) and stirred for 48 hours. The suspension was filtered throughcelite and concentrated to give the crude product. Purification bycolumn chromatography on silica gel (51 g silica, 60:1 CH₂Cl₂: CH₃OH)provided 942 mg (66% over three steps) of o-benzylic aldehydeintermediate as a yellow foam. The aldehyde from above (0.150 g, 0.378mmol) was stirred with allyl amine (42 μL, 0.968 mmol) in CH₃OH (2.5 mL)for 18 hours, then treated with NaBH4 (24 mg, 0.634 mmol). The mixturewas concentrated after 90 minutes. The residue was diluted with CH₂Cl₂(30 mL) and washed with brine (3×15 mL). The combined aqueous phase wasextracted with CH₂Cl₂ (1×15 mL). The combined organic phases were dried(Na₂SO₄), filtered and concentrated to give the crude product.Purification by radial chromatography on silica gel (2 mm plate, 100:1:1CH₂Cl₂: CH₃OH: NH₄OH) provided 53 mg (32%) of a white foam.

[0376] Using General Procedure D: Conversion of the foam from above (53mg, 0.121 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD11174 (77 mg, 88%) asa white solid. ¹H NMR (D₂O) δ1.83-1.99 (m, 1H), 2.19-2.40 (m, 2H),2.45-2.55 (m, 1H), 2.99-3.12 (m, 2H), 3.61 (d, 2H, J=6.5 Hz), 3.92 (d,1H, J=13.5 Hz), 4.12-4.20 (m, 2H), 4.36-4.43 (m, 2H), 4.58 (d, 1H,J=16.3 Hz), 5.44 (s, 1H), 5.89 (d, 1H, J=5.2 Hz), 5.77-5.91 (m, 1H),6.93 (t, 1H, J=7.5 Hz), 7.02 (d, 1H, J=7.9 Hz), 7.18 (t, 1H, J=7.7 Hz),7.43 (d, 1H, J=7.9 Hz), 7.51-7.56 (m, 2H), 7.58-7.64 (m, 2H), 7.92 (t,1H, J=6.8 Hz), 8.41 (d, 1H, J=8.4 Hz), 8.75 (d, 1H, J=5.8 Hz); ¹³C NMR(D₂O) δ20.43, 20.96, 27.90, 47.07, 49.16, 49.69, 53.30, 62.33, 113.95,124.80, 126.25, 126.93, 127.51, 129.38, 129.67, 130.31, 130.53, 130.96,132.10, 135.49, 139.88, 141.18, 148.44, 150.41, 150.73. ES-MS m/z 438(M+H). Anal. Calcd. for C₂₈H₃₁N₅.3.0HBr.2.2H₂O: C, 46.71; H, 5.38; N,9.73; Br, 33.30. Found: C, 46.79; H, 5.27; N, 9.62; Br, 33.17.

EXAMPLE: 47

[0377]

AMD11133: Preparation of(1H-Benzimidazol-2-ylmethyl)-[2-(R)-(2-aminopropionamindylmethyl)-benzyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt).

[0378] To a solution of N-t-butoxycarbonyl-l-alanine (37 mg, 0.195 mmol)in dichloromethane (5 mL) was added, in the following order:diisopropylethylamine (0.08 mL, 0.468 mmol), 1-hydroxybenzotriazole((HOBT) 32 mg, 0.234 mmol),(1H-Benzimidazol-2-ylmethyl)-(2-Aminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(62 mg, 0.156 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride ((EDAC) 45 mg, 0.234 mmol). The resulting solution wasthen stirred overnight at room temperature under nitrogen. The solutionwas then extracted with aqueous ammonium chloride, dried, concentratedand purified by silica gel flash chromatography using a 20:1dichloromethane:methanol solution as an eluent to afford(1H-Benzimidazol-2-ylmethyl)-{2-(R)-[2-(N-t-butoxycarbonyl)-aminopropionamidylmethyl]-benzyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amineas a mixture of two diastereomers in a yield of 61 mg (69%). ¹H NMR(CDCl₃) δ1.14 and 1.56 (d, total of 3H, J=6.9 Hz), 1.370 and 1.483 (s,total of 9H), 1.88 (m, 1H), 1.93 (m, 1H), 2.03 (m, 1H), 2.36 (m, 1H),2.75-2.86 (m, 2H), 3.74 (m, 3H), 3.91 (m, 2H), 4.05 and 4.41 (m, totalof 1H), 4.66 (m, 1H), 5.34 (m, 1H), 7.13 (m, 5H), 7.29-7.44 (m, 4H),7.68 (br s, 1H (NH)). 8.38 and 8.56 (m, total of 1H), 8.59 and 8.76 (d,total of 1H, J=4.9 Hz).

[0379](1H-Benzimidazol-2-ylmethyl)-{2-(R)-[2-(N-t-butoxycarbonyl)-aminopropionamidylmethyl]-benzyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(61 mg 0.107 mmol), was taken up in acetic acid (1 mL), to which asaturated solution of HBr in acetic acid (1 mL) was added. The mixturewas then stirred, precipitated and isolated as per procedure D to yieldAMD11133 as a white crystalline solid in a yield of 64 mg. ¹H NMR (D₂O)δ1.43 and 1.46 (d, total of 3H, J=6.9 Hz), 1.88 (m, 1H), 2.28 (m, 2H),2.46 (m, 1H), 3.00 (m, 2H), 3.81 (d, 1H, J=12.8 Hz), 4.03 (m, 2H), 4.21(d, 1H, J=12.8 Hz), 4.43-4.77 (m, 4H), 6.68 (m, 2H), 6.91 (m, 1H), 7.25(t, 1H, J=6.1 Hz), 7.51 (m, 4H), 7.88 (m, 1H), 8.28 (m, 1H), 8.68 (d,1H, J=4.8 Hz). ¹³C NMR (D₂O) 17.01, 20.43 and 20.67 (1C total), 27.89,40.78, 48.93 and 49.22 (1C total), 49.43, 53.87 and 54,46 (1C total),62.01 and 62.15 (1C total), 113.92 and 113.97 (2C total), 126.08, 126.74(2C), 128.03, 129.13, 131.45, 131.55, 133.92, 136.00, 139.91, 140.78,148.19 and 148.27 (1C total), 150.25 and 150.43 (1C total), 170.69 and170.91 (1C total). ES-MS m/z 469 (M+H); Anal. Calcd. for (C₂₈H₃₂N₆O×3.1HBr×1.1 H₂O×1.0 HOAc): C, 45.04; H, 5.21; N, 10.53; Br 31.04. Found: C,45.04; H, 5.19; N, 10.53; Br, 31.04.

EXAMPLE: 48

[0380]

AMD9872: Preparation of(1H-benzimidazol-2-ylmethyl)-[2-(1H-benzimidazol-2-ylmethyl)-aminobenzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine

[0381] Preparation of(5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)-amine

[0382] Using General Procedure B: To a solution of 2-aminobenzylamine(0.36 g, 2.9 mmol) and 6,7-dihydro-5H-quinolin-8-one (0.43 g, 2.9 mmol)in CH₂Cl₂ (15 mL) was added NaBH(OAc)₃ (0.92 g, 4.4 mmol) and themixture stirred at room temperature for 64 h. Purification of the crudematerial by column chromatography on silica gel (2% MeOH/CH₂Cl₂) gave(5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)-amine (0.39 g, 52%) asa yellow oil. 1H NMR (CDCl₃) δ1.80 (m, 1H), 1.94 (m, 2H), 2.17 (m, 1H),2.79 (m, 2H), 3.84 (m, 1H), 3.87 (d, 1H, J=11.7 Hz), 4.02 (d, 1H, J=12.0Hz), 6.64 (d, 1H, J=7.8 Hz), 6.67 (t, 1H, J=7.8 Hz), 7.09 (m, 3H), 7.38(d, 1H, J=3.0 Hz), 8.38 (d, 1H, J=3.9 Hz).

[0383] Using the general N-alkylation procedure: A solution of(5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)-amine (0.16 g, 0.6mmol), N,N-diisopropylethylamine (0.32 mL, 1.8 mmol) and potassiumiodide (10 mg, 40 μmol) in CH₃CN (6 mL) was reacted with1-(N-tert-butoxycarbonyl)-2-chloromethylbenzimidazole (0.32 g, 1.2 mmol)at 70° C. for 16 h to yield after purification by column chromatographyon silica gel (CH₂Cl₂/MeOH, 250:1) the N-alkylated product (0.16 g, 37%)as a pale yellow solid. ¹H NMR (CDCl₃) δ1.56 (s, 9H), 1.70 (s, 1OH),1.95 (m, 2H), 2.48 (m, 1H), 2.65 (m, 2H), 4.23 (d, 1H, J=3.0 Hz), 4.27(d, 1H, J=8.1 Hz), 4.29 (m, 1H), J=3.0 Hz), 4.53 (d, 1H, J=8.4 Hz), 4.93(m, 2H), 6.55 (m, 2H), 6.98 (m, 2H), 7.10 (d, 1H, J=7.8 Hz), 7.20-7.32(mn, 4H), 7.55 (m, 1H), 7.68 (m, 1H), 7.82 (mn, 2H), 7.90 (m, 1H), 8.44(d, 1H, J=3.2 Hz).

[0384] A solution of the material from above (0.17 g, 0.24 mmol) inCH₂Cl₂/TFA (1:1, 2 mL) was stirred for 0.5 h and the solutionconcentrated under reduced pressure. The reaction was partitionedbetween 15% aqueous NaOH (5 mL) and CH₂Cl₂ (5 mL), the phases separatedand the organic extract dried (MgSO₄), filtered, concentrated andpurified by radial chromatography on silica gel (MeOH/NH₄OH/CH₂Cl₂;1:1:98) to give AMD9872 (48 mg, 40%) as a pale yellow solid. ¹H NMR(CDCl₃) δ1.71 (br, 1H), 2.09 (m, 2H), 2.29 (br, 1H), 2.73 (m, 1H), 2.85(m, 1H), 3.81 (d, 1H, J=12.9 Hz), 3.90 (d, 1H, J=12.6 Hz), 4.06 (d, 2H,J=6.9 Hz), 4.09 (m, 1H), 4.77 (s, 2H), 6.50 (d, 1H, J=8.1 Hz), 6.62 (t,1H, J=7.4 Hz), 6.94 (br, 1H), 7.04 (t, 1H, J=7.8 Hz), 7.05-7.25 (br m,6H), 7.43 (d, 1H, J=7.8 Hz), 7.66 (br, 3H), 8.41 (d, 1H, J=3.9 Hz). ¹³CNMR (CDCl₃) δ21.45, 21.80, 29.23, 42.32, 48.18, 54.10, 59.88, 110.27(2C), 117.06 (2C), 121.71, 122.25 (5C), 122.48 (2C), 129.23 (2C), 130.91(2C), 135.18, 137.70 (2C), 146.91 (2C), 147.16, 154.00, 154.19, 157.03.ES-MS m/z 514 (M+H). Anal. Calcd. for C₃₂H₃₁N₇.1.0CH₂Cl₂.0.3C₆H₁₄: C,66.57; H, 5.98; N, 15.60. Found: C, 66.61; H, 5.78; N, 15.51.

EXAMPLE: 49

[0385]

AMD9883: Preparation of(2-aminobenzyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine

[0386] Using the general N-alkylation procedure: A solution of(5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)-amine (0.20 g, 0.8mmol), N,N-diisopropylethylamine (0.14 mL, 0.8 mmol) and potassiumiodide (5 mg, 30 μmol) in CH₃CN (8 mL) was reacted with1-(N-tert-butoxycarbonyl)-2-chloromethylbenzimidazole (0.145 g, 0.55mmol) at 70° C. for 16 h to yield after purification by radialchromatography on silica gel (MeOH/NH₄OH/CH₂Cl₂; 1:1:98) the monoN-alkylated product (65 mg, 25%) as a pale yellow solid. ¹H NMR (CDCl₃)δ1.61 (s, 10H), 1.94 (m, 2H), 2.03 (br, 1H), 2.67 (m, 2H), 3.98 (d, 1H,J=12.3 Hz), 4.22 (m, 1H), 4.30 (d, 2H, J=9.9 Hz), 4.37 (d, 1H, J=11.1Hz), 5.44 (br, 2H), 6.53 (m, 2H), 6.90 (m, 1H), 6.97 (t, 1H, J=6.7 Hz),7.06 (d, 1H, J=7.5 Hz), 7.17 (d, 1H, J=7.5 Hz), 7.25 (d, 2H, J=7.2 Hz),7.61 (m, 1H), 7.81 (m, 1H, J=3.6 Hz), 8.40 (d, 1H, J=4.5 Hz).

[0387] A solution of the material from above (65 mg, 0.13 mmol) inCH₂Cl₂/TFA (1:1, 1 mL) was stirred for 0.5 h and the solutionconcentrated under reduced pressure. The reaction was partitionedbetween 15% aqueous NaOH (3 mL) and CH₂Cl₂ (5 mL), the phases separatedand the organic extract dried (MgSO₄), filtered, concentrated andpurified by radial chromatography on silica gel (MeOH/NH/CH₂Cl₂;1:1:150) to give AMD9883 (33 mg, 64%) as a pale yellow solid. ¹H NMR(CDCl₃) δ1.71 (br, 1H), 2.05 (m, 2H), 2.32 (br, 1H), 2.70 (m, 1H), 2.85(m, 1H), 3.65 (d, 1H, J=12.6 Hz), 3.80 (d, 1H, J=12.6 Hz), 4.05 (m, 1H),4.08 (d, 2H, J=4.8 Hz), 6.63 (t, 1H, J=8.7 Hz), 6.64 (t, 1H, J=6.6 Hz),7.03 (t, 2H, J=7.2 Hz), 7.17 (m, 3H), 7.42 (d, 1H, J=7.2 Hz), 7.54 (br,2H), 8.53 (d, 1H, J=4.2 Hz). ¹³C NMR (CDCl₃) δ21.64, 21.91, 29.55,48.22, 53.20, 60.93, 111.08, 116.59, 118.09, 119.14, 122.05 (4C),122.52, 122.83, 129.19, 131.83, 135.22, 137.98, 147.09, 147.17, 156.04,157.47. ES-MS m/z 384 (M+H). Anal. Calcd. for C₂₄H₂₅N₅.0.6CH₂Cl₂: C,67.49; H, 6.04; N, 15.97. Found C, 6.21; N, 15.57.

EXAMPLE: 50

[0388]

AMD9736: Preparation of(1H-Benzimidazol-2-ylmethyl)-(2-cyano-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0389] The intermediate[1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(2-cyano-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(see AMD9720) (72 mg, 0.145 mmol) was refluxed in 6N HCl (5 mL) for 16h. The solvent was removed under reduced pressure and the resultant saltdissolved in distilled water (0.8 mL) and ethanol (95%, 0.8 mL) andtreated with NaOH (0.148 g, 3.69 mmol). The mixture was heated to 90° C.for 2 h and stirred at room temperature for 64 h. The biphasic systemwas diluted with water (4 mL) and extracted with ether (3×10 mL). Thecombined organic phases were dried Na₂SO₄), filtered and concentratedunder reduced pressure to give a white powder. Purification of the solidby radial chromatography (1 mm TLC plate, 60:1:1 CH₂Cl₂/CH₃OH/NH₄OH)gave the desired freebase (48 mg, 84%).

[0390] Following General Procedure D: Conversion of the material fromabove (48 mg) to the hydrobromide salt gave AMD9736 (45 mg, 64%). ¹H NMR(D₂O) δ1.85-2.01 (m, 1H), 2.17-2.52 (m, 3H), 2.98-3.14 (m, 2H), 3.95 (d,1H, J=13.2 Hz), 4.15 (d, 1H, J=13.2 Hz), 4.46 (d, 1H, J=16.3 Hz), 4.63(d, 1H, J=16.6 Hz), 6.96 (t, 1H, J=7.7 Hz), 7.27 (t, 1H, J=7.7 Hz), 7.35(t, 1H, J=8.1 Hz), 7.49-7.60 (m, 4H), 7.92 (dd, 1H, J=7.9, 5.5 Hz), 8.40(d, 1H, J=7.8 Hz), 8.71 (d, 1H, J=5.8 Hz). ¹³C NMR (D2O) δ18.14, 18.68,25 47.43, 53.07, 60.81, 109.76, 111.60 (2 carbons), 116.68, 123.81,124.55 (2 carbons), 126.70, 128.29, 129.19, 131.29, 131.46, 137.66,137.84, 138.58, 145.88, 147.73, 148.64. IR (CsI) ν2224 (C≡N). ES-MS m/z394 (M+H) Anal Calc. for C₂₅H₂₃N₅.2.0HBr.1.3H₂O: C, 51.88; H, 4.81; N,12.10; Br, 27.61. Found: C, 51.86; H, 4.86; N, 11.78; Br, 27.78.

EXAMPLE: 51

[0391]

AMD11091: Preparation of2-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-6-methoxy-benzoicacid ethyl ester (hydrobromide salt).

[0392] To a solution of ethyl 6-methylsalicylate (1.27 g, 6.97 mmol) inTHF (35 mL) was added lithium hydroxide monohydrate (0.594 g, 14.2 mmol)followed by dimethyl sulfate (1.00 mL, 10.6 mmol). The resultant mixturewas heated to reflux for 1 hour then cooled to room temperature. Themixture was diluted with diethyl ether (70 mL), washed with saturatedaqueous NaHCO₃ (4×10 mL), dried (MgSO4) and concentrated. Purificationof the crude material by column chromatography on silica gel (9:1hexanes-EtOAc) provided 1.23 g (91%) of ethyl 2-methoxy-6-methylbenzoateas a white solid. ¹H NMR (CDCl₃) δ1.38 (t, 3H, J=7.2 Hz), 2.30 (s, 3H),3.82 (s, 3H), 4.40 (q, 2H, J=7.2 Hz), 6.76 (d, 1H, J=8.4 Hz), 6.79 (d,1H, J=7.8 Hz), 7.23 (dd, 1H, J=7.8, 8.4 Hz).

[0393] To a solution of ethyl 2-methoxy-6-methylbenzoate (0.813 g, 4.19mmol) in CCl₄ (8 mL) was added recrystallized N-bromosuccinimide (0.751g, 4.22 mmol) followed by benzoyl peroxide (52 mg, 0.22 mmol). Theresultant mixture was heated to reflux for 90 minutes then cooled toroom temperature. The mixture was diluted with diethyl ether (50 mL),filtered through filter paper, and the filtrate was concentrated.Purification of the crude material by column chromatography (8:1hexanes-EtOAc) provided 0.68 g (60%) of ethyl6-(bromomethyl)-2-methoxybenzoate as a colorless oil. ¹NMR (CDCl₃) δ1.42(t, 3H, J=7.2 Hz), 3.84 (s, 3H), 4.45 (q, 2H, J=7.2 Hz), 4.50 (s, 2H),6.89 (d, 1H, J=8.4 Hz), 7.01 (d, 1H, J=7.2 Hz), 7.34 (dd, 1H, J=7.2, 8.4Hz).

[0394] To a solution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.409 g, 1.08 mmol) in CH₃CN (5 mL) was added N,N-diisopropylethylamine(0.38 mL, 2.18 mmol) followed by a solution of ethyl6-(bromomethyl)-2-methoxybenzoate (0.454 g, 1.66 mmol) in CH₃CN (6 mL).The resultant mixture was heated to 60° C. for 22 hours then cooled toroom temperature. The mixture was concentrated and the residue waspartitioned between CH₂Cl₂ (50 mL) and brine (10 mL). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×10 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by column chromatography on silicagel (25:1 CH₂Cl₂—CH₃OH) followed a further chromatographic purificationby column chromatography on silica gel (2:1 hexanes-EtOAc) and radialchromatography on silica gel (2 mm plate, 100:1:1 CH₂Cl₂—CH₃OH—NH₄OH)provided 0.38 g (62%) of a white solid.

[0395] Using General Procedure D: Conversion of the solid from above (55mg, 0.10 mmol) to the hydrobromide salt with simultaneous removal of theBOC-protecting group, followed by re-precipitation of the intermediatesolid from methanol/ether gave AMD11091 (35 mg, 51%) as a gold solid. ¹HNMR (D₂O) δ1.23 (t, 3H, J=7.2 Hz), 1.82-1.90 (m, 1H), 2.17-2.28 (m, 2H),2.34-2.40 (m, 1H), 3.00 (br s, 2H), 3.45 (s, 3H), 3.69 (d, 1H, J=12.6Hz), 3.82 (d, 1H, J=12.6 Hz), 4.25-4.37 (m, 2H), 4.40 (d, 1H, J=15.9Hz), 4.52 (d, 1H, J=15.9 Hz), 4.68 (dd, 1H, J=6.0, 9.3 Hz), 6.54 (d, 1H,J=8.4 Hz), 6.99 (d, 1H, J=7.5 Hz), 7.15 (dd, 1H, J=7.5, 8.4 Hz),7.50-7.53 (m, 2H), 7.59-7.62 (m, 2H), 7.90 (dd, 1H, J=6.3, 7.5 Hz), 8.36(d, 1H, J=7.8 Hz), 8.77 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ13.77, 20.42,20.79, 27.77, 49.29, 53.67, 56.45, 62.55, 63.59, 112.11, 113.95, 123.03,123.84, 126.07, 126.74, 130.62, 131.76, 134.36, 139.77, 140.89, 148.12,150.49, 150.81, 156.10, 169.70. ES-MS m/z 471 (M+H). Anal. Calcd. forC₂₈H₃₀N₄O₃.2.2HBr.1.7H₂O: C, 49.52; H, 5.28; N, 8.25; Br, 25.88. Found:C, 49.89; H, 5.33; N, 8.19; Br, 25.53.

EXAMPLE: 52

[0396]

AMD9837: Preparation of(6-aminopyridin-3-ylmethyl)-(benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(hydrobromide salt)

[0397] Preparation of6-(N-tert-butoxycarbonylamino)-3-hydroxymethylpyridine

[0398] A solution of 6-aminonicotinic acid (2.0 g, 14.4 mmol) inanhydrous EtOH (70 mL) and concentrated sulfuric acid (14 mL) was heatedto reflux for 16 h. The solution was concentrated under reducedpressure, neutralized with saturated aqueous Na₂CO₃ (50 mL) andextracted with CH₂Cl₂ (3×50 mL). The combined organic phases were dried(MgSO₄), filtered and concentrated to give 6-aminonicotinic acid ethylester (2.18 g, 92%) as a white powder. ¹H NMR (CDCl₃) δ1.37 (t, 3H,J=6.0 Hz), 4.34 (q, 2H, J=7.0 Hz), 4.89 (br s, 2H (NH₂)), 6.46 (d, 1H,J=7.5 Hz), 8.02 (d, 1H, J=7.5 Hz), 8.73 (s, 1H).

[0399] To a solution of 6-aminonicotinic acid ethyl ester (1.18 g, 7.1mmol) in anhydrous THF (24 mL) was added a solution of lithium aluminumhydride (0.41 g, 10.6 mmol) in THF (12 mL) at 0° C. over 10 min and themixture stirred for 1.5 h. To the reaction was added sequentially 0.5 mLH₂O, 0.5 mL 15% aqueous NaOH and 1.5 mL H₂O and the resultant slurry wasfiltered. The filtrate was dried (MgSO₄), filtered, concentrated andpurified by column chromatography (10% MeOH/CH₂Cl₂) to give6-amino-3-hydroxymethylpyridine (0.61 g, 69%) as colorless crystals. ¹HNMR (MeOD) δ6 3.31 (s, 1H (OH)), 4.43 (s, 2H), 6.58 (d, 1H, J=8.4 Hz),7.48 (d, 1H, J=8.7 Hz), 7.85 (s, 1H).

[0400] To a solution of 6-amino-3-hydroxymethylpyridine (0.30 g, 2.4mmol) in anhydrous tert-butanol (12.4 g, 16 mL) was addeddi-tert-butyldicarbonate (0.58 g, 2.7 mmol) and the mixture stirred 16 hat 40° C. The reaction was concentrated under reduced pressure and thecrude residue purified by column chromatography on silica gel (7.5%MeOH/CH₂Cl₂) to afford the title alcohol (0.42 g, 77%) as a white solid.¹H NMR (CDCl₃) δ1.54 (s, 9H), 1.74 (t, 1H (OH), J=6.0 Hz), 4.65 (d, 2H,J=6.0 Hz), 7.68 (d, 1H, J=9.0 Hz), 7.83 (br s, 1H (NH)), 7.95 (d, 1H,J=9.0 Hz), 8.24 (s, 1H).

[0401] Using General Procedure C: To a solution of6-(N-tert-butoxycarbonylamino)-3-hydroxymethylpyridine (0.42 g, 1.9mmol) and triethylamine (0.40 mL, 2.8 mmol) in CH₂Cl₂ (19 mL) was addedmethanesulfonyl chloride (0.20 mL, 2.4 mmol) and the mixture stirred atroom temperature for 1 h. Purification of the crude product by columnchromatography on silica gel (4% MeOH/CH₂Cl₂) afforded the desiredmesylate (0.23 g, 42%). ¹H NMR (CDCl₃) δ1.54 (s, 9H), 3.37 (s, 3H), 4.40(s, 2H), 7.68 (d, 1H, J=9.0 Hz), 7.95 (d, 1H, J=9.0 Hz), 8.11 (br s,1H), 8.25 (s, 1H).

[0402] Using General Procedure for N-Alkylation: A solution of themesylate from above (0.22 g, 0.8 mmol), N,N-diisopropylethylamine (0.20mL, 1.2mmol) and potassium chloride (10 mg, 0.04 mmol) in CH₃CN (8 mL)was reacted with(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.30 g, 0.8 mmol) at 70° C. for 16 h. Purification of the crudematerial by radial chromatography on silica gel (MeOH/NH₄OH/CH₂Cl₂;1:1:98) gave the N-alkylated product (180 mg, 40%) as a flaky whitesolid. ¹H NMR (CDCl₃) δ1.49 (s, 9H), 1.70 (br s, 10H), 1.96 (m, 2H),2.13 (m, 1H) 2.70 (m, 2H), 3.76 (d, 1H, J=15.0 Hz), 4.03 (d, 1H, J=15.0Hz), 4.25 (m, 1H), 4.58 (s, 2H), 7.00 (m, 1H), 7.20 (m, 2H), 7.30 (s,1H), 7.66 (m, 4H), 8.04 (s, 2H), 8.43 (dd, 1H, J=3.0 Hz).

[0403] Using General Procedure D: Conversion of the solid from above (30mg) to the hydrobromide salt with simultaneous removal of the Boc groupprovided AMD9837 (0.034 g) as a white solid. ¹H NMR (D₂O) δ1.90 (br m,1H), 2.20 (m, 2H), 2.40 (br m, 1H), 3.02 (br m, 2H), 3.70 (d, 1H, J=13.5Hz), 3.83 (d, 1H, J=13.5 Hz), 4.37 (d, 1H, J=15.9 Hz), 4.58 (d, 1H,J=16.2 Hz), 4.75 (m, 1H), 6.62 (d, 1H, J=9.3 Hz), 7.53 (d, 1H, J=1.5Hz), 7.57 (dd, 2H, J=3.0, 6.0 Hz), 7.68 (d, 1H, J=2.1 Hz), 7.70 (m, 2H),7.92 (dd, 1H, J=6.0, 7.8 Hz), 8.40 (d, 1H, J=7.2 Hz), 8.75 (d, 1H, J=4.8Hz); ¹³C NMR (D₂O)δ20.38, 20.92, 27.86, 49.32, 53.02, 62.53, 114.11(4C), 121.78, 126.19, 127.24 (2C), 130.91, 134.41, 140.07 (2C), 141.11,145.36, 148.33, 150.36, 151.72. ES-MS m/z 385 (M+H). Anal. Calcd. forC₂₃H₂₄N₆.2.9HBr.2.1 H₂O: C, 42.21; H, 4.78; N, 12.84; Br, 35.10. Found:C, 42.29; H, 4.71; N, 12.58; Br, 35.09.

EXAMPLE: 53

[0404]

AMD9840: Preparation of(2-aminopyridin-3-ylmethyl)-(benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-8-quinolinyl)-amine(hydrobromide salt)

[0405] Preparation of 2-aminonicotinic aldehyde

[0406] A solution of 2-aminonicotinic acid (2.0 g, 14.4 mmol) inanhydrous EtOH (70 mL) and concentrated sulfuric acid (14 mL) was heatedto reflux for 16 h. The solution was concentrated under reducedpressure, neutralized with saturated aqueous Na₂CO₃ (50 mL) andextracted with CH₂Cl₂ (3×50 mL). The combined organic phases were dried(MgSO₄), filtered and concentrated to give 2-aminonicotinic acid ethylester as a yellow solid (1.74 g, 74%). ¹H NMR (CDCl₃) δ1.40 (t, 3H,J=6.0 Hz), 4.34 (q, 2H, J=7.0 Hz), 6.41 (br s, 2H (NH₂)), 6.63 (m, 1H),8.14 (d, 1H, J=7.8 Hz), 8.22 (s, 1H).

[0407] To a solution of 2-aminonicotinic acid ethyl ester (1.74 g, 10.5mmol) in anhydrous THF (35 mL) was added a solution of lithium aluminumhydride (0.60 g, 15.7 mmol) in THF (17 mL) at 0° C. over 15 min and themixture stirred for 1.5 h. To the reaction was added sequentially 0.6 mLH₂O, 0.6 mL 15% aqueous NaOH and 1.8 mL H₂O and the resultant slurry wasfiltered. The filtrate was dried (MgSO₄), filtered, concentrated andpurified by column chromatography (10% MeOH/CH₂Cl₂) to give2-amino-3-hydroxymethylpyridine (1.03 g, 79%) as a yellow crystallinesolid. ¹H NMR (CDCl₃) δ3.14 (br s, 1H (OH)), 4.60 (s, 2H), 5.00 (br s,1H (NH)), 6.59 (t, 1H, J=6.0 Hz), 7.28 (d, 1H, J=7.5 Hz), 7.94 (d, 1H,J=7.5 Hz).

[0408] The alcohol (0.10 g, 0.8 mmol) from above was dissolved in CH₂Cl₂(8 mL), treated with activated MnO₂ (0.70 g, 8 mmol) and stirred at roomtemperature for 1.5 h. The mixture was filtered through celite© and thecake was washed with CH₂Cl₂. The solvent was removed from the filtrateunder reduced pressure and provided 2-aminonicotinic aldehyde (0.10 g,99%) as a pale yellow crystalline solid. ¹H NMR (CDCl₃) δ6.75 (t, 1H,J=6.0 Hz), 7.81 (d, 1H, J=7.5 Hz), 8.27 (d, 1H, J=4.5 Hz), 9.86 (s, 1H,(CHO)).

[0409] Using General Procedure B: To a solution of 2-aminonicotinicaldehyde (47 mg, 0.4 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(132 mg, 0.35 mmol) in CH₂Cl₂ (4 mL) was added sodiumtriacetoxyborohydride (126 mg, 0.59 mmol) and the mixture stirred atroom temperature for 16 h. Purification of the crude product by columnchromatography on silica gel (2% MeOH/CH₂Cl₂) gave the desiredN-alkylated product (68 mg, 40%) as a white solid. ¹H NMR (CDCl₃) δ1.58(s, 9H), 1.62 (m, 1H), 1.91 (m, 2H), 2.17 (m, 1H), 2.64 (m, 2H,), 3.93(d, 1H, J=12.0 Hz), 4.15 (m, 1H), 4.26 (d, 2H, J=3.0 Hz), 4.38 (d, 1H,J=12.0 Hz), 6.40 (t, 1H, J=4.5 Hz), 6.47 (br s, 2H), 6.97 (m, 1H), 7.27(m, 4H), 7.61 (m, 1H), 7.84 (m, 2H), 8.40 (d, 1H, J=3.0 Hz).

[0410] Using General Procedure D: Conversion of the material from above(25 mg) to the hydrobromide salt with simultaneous removal of the Bocgroup provided AMD9840 (0.025 g) as a white solid. ¹H NMR (D₂O) δ1.87(br m, 1H), 2.18 (m, 2H), 2.46 (br m, 1H), 2.98 (br m, 2H), 3.95 (d, 1H,J=14.1 Hz), 4.07 (d, 1H, J=14.1 Hz), 4.33 (d, 1H, J=16.2 Hz), 4.49 (d,1H, J=15.9 Hz), 4.74 (m, 1H), 6.64 (t, 1H, J=6.9 Hz), 7.25 (dd, 1H,J=1.5, 6.3 Hz), 7.55 (m, 2H), 7.66 (m, 2H), 7.83 (t, 1H, J=6.9 Hz), 7.93(dd, 1H, J=1.5, 7.4 Hz), 8.28 (d, 1H, J=7.2 Hz), 8.70 (d, 1H, J=5.1 Hz);¹³C NMR (D₂O) δ20.45, 20.68, 27.95, 48.36, 52.51, 62.20, 113.24, 114.03(2C), 120.49, 120.73, 126.09, 127.17 (2C), 130.89, 135.44, 140.70,140.81, 146.12 (2C), 147.61, 150.32, 150.71. ES-MS m/z 385 (M+H). Anal.Calcd. for C₂₃H₂₄N₆.3.0HBr.2.2H₂O: C, 41.49; H, 4.74; N, 12.62; Br,35.95. Found: C, 41.56; H, 4.61; N, 12.38; Br, 35.94.

EXAMPLE: 54

[0411]

AMD9681: Preparation ofN-(4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-guanidine(hydrobromide salt)

[0412] To a solution of 4-aminobenzyl alcohol (0.127 g, 1.03 mmol) indry THF (1 mL) was added N.N′-bis-(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (TetrahedronLett. 1993, 34, 3389) and the resultant mixture was stirred at roomtemperature for 26 h. The mixture was diluted with hexanes (1 mL) andfiltered through a short silica gel column (100% hexanes followed by 1:1hexanes/ethyl acetate). The appropriate fractions were concentrated toprovide N,N′-bis-(tert-butoxycarbonyl)-N″-(4-hydroxymethyl-phenyl)-guanidine(0.309 g, 85%) as a white solid.

[0413] The alcohol (0.282 g, 0.771 mmol) from above was dissolved inCH₂Cl₂ (7 mL), treated with activated MnO₂ (0.696 g, 8.01 mmol) andstirred at room temperature overnight. The mixture was filtered throughcelite© and the cake was washed with CH₂Cl₂. The solvent was removedfrom the filtrate under reduced pressure and provided N,N′-bis-(tert-butoxycarbonyl) -N″-(4-formyl-phenyl)-guanidine (0.260 g,93%) as a white solid. ¹H NMR (CDCl₃) δ1.53 (s, 9H), 1.55 (s, 9H), 7.85(s, 4H), 9.93 (s, 1H), 10.34 (br s, 1H).

[0414] Using General Procedure B: Reaction of N,N′-bis-(tert-butoxycarbonyl)-N″-(4-formyl-phenyl)-guanidine (0.167 g,0.49 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.151 g, 0.42 mmol) with NaBH(OAc)₃ (0.184 g, 0.87 mmol) in CH₂Cl₂ (4mL) for 4.5 hours followed by purification of the crude material byradial chromatography on silica gel (2 mm plate, 20:1:1CH₂Cl₂/CH₃OH/NH₄OH) provided the desired tertiary amine (0.101 g, 33%)as a white solid.

[0415] Using General Procedure D: Conversion of the white solid (101 mg)to the hydrobromide salt with simultaneous removal of the BOC-protectinggroup, followed by re-precipitation of the intermediate solid frommethanol/ether, gave AMD9681 (66 mg) as a white solid. ¹H NMR (D₂O)δ1.81-1.92 (m, 1H), 2.19-2.30 (m, 2H), 2.41-2.46 (m, 1H), 3.01 (br s,2H), 3.78 (d, 1H, J=12.9 Hz), 3.84 (d, 1H, J =12.9 Hz), 4.43 (d, 1H,J=16.5 Hz), 4.62 (d, 1H, J=16.5 Hz), 4.72-4.79 (m, 1H, overlaps withHOD), 6.84 (d, 2H, J=8.1 Hz), 7.21 (d, 2H, J=8.1 Hz), 7.49-7.53 (m, 2H),7.56-7.60 (m, 2H), 7.91 (dd, 1H, J=6.0, 7.8 Hz), 8.38 (d, 1H, J=7.8 Hz),8.73 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ20.4 20.86, 27.83, 50.03, 56.40,62.98, 113.84, 124.65, 126.08, 126.76, 130.47, 131.50, 134.21, 135.70,139.65, 141.00, 148.26, 148.28, 150.83, 151.77; ES-MS m/z 426 (M+H).Anal. Calcd. for C₂₅H₂₇N₇.3.0HBr.3.4 H₂O: C, 41.16; H, 5.08; N, 13.44;Br, 32.86. Found: C, 41.12; H, 4.86; N, 13.32; Br, 32.81.

EXAMPLE: 55

[0416]

AMD9730: Preparation of(4-Amino-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0417] Preparation of (4-formyl-phenyl)-carbamic acid tert-butyl ester

[0418] A solution of 4-aminobenzyl alcohol (607 mg, 4.93 mmol) anddi-t-butyl dicarbonate (1.3 g, 6.0 mmol) in THF (16 mL) was stirred atroom temperature for 24 h then concentrated. Purification of the crudematerial on silica gel (30% EtOAc/hexanes) gave a colourless oil (906mg, 82%). ¹H NMR (CDCl₃) δ1.52 (s, 9H), 4.63 (d, 2H, J=5.7 Hz), 6.48 (brs, 1H), 7.32 (m, 4H).

[0419] To a solution of the alcohol from above (200 mg, 0.896 mmol) inCH₂Cl₂ (9 mL) was added activated MnO₂ (916 mg, 8.96 mmol) and themixture stirred at room temperature overnight. The reaction mixture wasfiltered through Celite and the cake was washed with CH₂Cl₂. The solventwas removed from the filtrate under reduced pressure to give the titlecompound as colourless crystals (170 mg, 86%). ¹H NMR (CDCl₃) δ1.54 (s,9H), 6.73 (br s, 1H), 7.54 (d, 2H, J=9 Hz), 7.83 (d, 2H, J=9 Hz), 9.90(s, 1H).

[0420] Using General Procedure B: To a solution of[1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(83 mg, 0.22 mmol) and (4-formyl-phenyl)-carbamic acid tert-butyl ester(66 mg, 0.30 mmol) in THF (3 mL) was added acetic acid (0.017 mL, 0.30mmol) and NaBH(OAc)₃ (190 mg, 0.896 mmol) and the mixture stirred atroom temperature for 4 h. Purification of the crude yellow oil bychromatography on silica gel (300:5:1 CH₂Cl₂/MeOH/NH₄OH) gave acolourless foam (128 mg).

[0421] A solution of the foam from above in 1:1 trifluoroaceticacid/CH₂Cl₂ (4 mL) was stirred at room temperature for 45 min thenconcentrated. The residue was partitioned between CH₂Cl₂ (10 mL) andsaturated aqueous NaHCO₃ (10 mL) and the aqueous phase was extractedwith CH₂Cl₂. The combined organic phases were dried (MgSO₄), filteredand concentrated under reduced pressure. Purification of the crudematerial by chromatography on silica gel (600:5:1 EtOAc/MeOH/NH₄OH) gavea colourless foam (49 mg, 53%).

[0422] Using General Procedure D: Conversion of the colourless foam fromabove (49 mg, 0.13 mmol) to the hydrobromide salt gave AMD9730 (56 mg,67%) as a yellow solid. ¹H NMR (D₂O) δ1.88 (m, 1H), 2.26 (m, 2H), 2.44(m, 1H), 3.02 (m, 2H), 3.83 (d, 1H, J=13 Hz), 3.89 (d, 1H, J=13 Hz),4.46 (d, 1H, J=16 Hz), 4.64 (d, 1H, J=16 Hz), 4.79 (m, 1H), 6.95 (d, 2H,J=8.1 Hz), 7.29 (d, 2H, J=8.4 Hz), 7.51-7.63 (m, 4H), 7.91 (m, 1H), 8.38(d, 1H, J=7.8 Hz), 8.74 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ20.45, 20.86,27.85, 50.06, 56.31, 62.82, 113.94, 122.85, 126.12, 126.85, 130.03,130.50, 131.58, 137.51, 139.70, 140.98, 148.28, 150.75, 151.51. ES-MSm/z 384 (M+H). Anal Calcd for (C₂₄H₂₅N₅) 3.0(HBr) 1.6(H₂O): C, 44.01; H,4.80; N, 10.69; Br, 36.59. Found: C, 43.84; H, 4.86; N, 10.40; Br,36.85.

EXAMPLE: 56

[0423]

AMD9774: Preparation ofN′-({[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-phenyl)-N,N-dimethylformamidine

[0424] Preparation of O-methanesulfonyl-4-(t-butoxycarbonyl)-aminobenzylalcohol

[0425] Using General Procedure C: To a solution of4-(t-butoxycarbonyl)-aminobenzyl alcohol (446 mg, 2 mmol) in CH₂Cl₂ (10mL) was added methanesulfonyl chloride (0.23 mL, 3 mmol) andtriethylamine (0.56 mL, 4 mmol). The solution was stirred for 60 min atroom temperature. Purification of the crude product by chromatography onsilica gel (2% MeOH/CH₂Cl₂) gave the title compound (320 mg, 56%) as anoil. ¹H NMR (CDCl₃) δ3.14 (s, 3H), 4.39 (s, 2H), 6.53 (br s, 1H (NH)),7.31 (m, 4H).

[0426] Using the general N-alkylation procedure: To a solution of themesylate from above (213 mg, 0.75 mmol) and N,N-diisopropylethylamine(0.178 mL, 1.0 mmol) in CH₃CN (10 mL) was added(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(210 mg, 0.55 mmol) and the mixture stirred at 60° C. for 4 h.Purification of the crude product by chromatography on silica gel (20:1CH₂Cl₂/MeOH) gave(1H-N-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-[4-(t-butoxycarbonylamino)-benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(126 mg, 39%). ¹H NMR (CDCl₃) δ1.41 (s, 9H), 1.68 (s, 9H), 2.03 (m, 3H),2.20 (m, 1H), 2.75 (m, 2H), 3.83 (m, 1H) 3.99 (m, 1H), 4.30 (dd, 1H,J=8.4, 6.5 Hz), 4.61 (m, 2H), 6.26 (br s, 1H (NH)), 7.04 (m, 2H), 7.26(m, 5H), 7.31 (m, 2H), 7.63 (m, 2H), 8.44 (m, 1H).

[0427] To a solution of(1H-N-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-[4-(t-butoxycarbonylamino)-benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(62 mg, 0.106 mmol) in CH₂Cl₂ (2 mL) was added trifluoroacetic acid (1mL). The mixture was stirred at room temperature for 2 h, thenconcentrated. The residue was taken up in CH₂Cl₂, washed with 15% NaOH(3 mL) and extracted repeatedly with CH₂Cl₂. The combined organicfractions were dried over anhydrous sodium sulfate, filtered andconcentrated. The crude(1H-benzimidazol-2-ylmethyl)-[4-aminobenzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-aminewas then added to a solution of 2-pyridinesulfonyl chloride (27 mg, 0.15mmol) in DMF (1 mL). The resulting solution was stirred at roomtemperature for 30 min. The mixture was then concentrated, taken up inCH₂Cl₂ and washed with aqueous potassium carbonate. The organic fractionwas then dried over anhydrous sodium sulfate, filtered, concentrated andpurified by chromatography on silica gel (10:1:0.1 CH₂Cl₂:MeOH:NH₄OH) toaffordN′-({[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-phenyl)-N,N-dimethylformamidine (21 mg, 47%). ¹H NMR (CDCl₃) δ1.69 (m, 1H), 2.01(m, 3H), 2.25 (m, 1H), 2.73 (m, 2H), 2.93 (s, 3H), 3.60 (s, 3H), 3.62(d, 1H, J=13.2 Hz), 3.68 (d, 1H, J =13.2 Hz), 3.98 (d, 1H, J =16.2 Hz),4.01 (m, 1H), 4.12 (d, 1H, J=16.2 Hz), 6.80 (d, 2H, J=8.1 Hz), 7.16 (m,4H), 7.26 (d, 1H, J=8.1 Hz), 7.38 (m, 2 H), 7.40 (br s, 1H), 8.55 (d,1H, J =4.8 Hz).

[0428] Using General Procedure D: Conversion of theN′-({[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-phenyl)-N,N-dimethylformamidine(21 mg, 0.047 mmol) to the hydrobromide salt gave AMD9774 (14 mg) as awhite solid. ¹H NMR (D₂O). δ1.91 (m, 1H), 2.29 (m, 2H), 2.43 (m, 1H),3.05 (m, 2H), 3.13 (s, 3H), 3.37 (s, 3H), 3.79 (d, 1H, J=12.3 Hz), 3.86(d, 1H, J=12.3 Hz), 4.44 (d, 1H, J=16.5 Hz), 4.63 (d, 1H, J=16.5 Hz),4.82 (m, 1H), 6.82 (d, 2H, J=8.1 Hz), 7.22 (d, 2H, J=8.1 Hz), 7.50-7.63(m, 4H), 7.95 (dd, 1H, J=7.8, 5.7 Hz), 8.41 (d, 1H, J=7.8 Hz), 8.78 (d,1H, J=5.7 Hz). ¹³C NMR (D₂O) δ20.45, 21.01, 27.86, 37.17, 44.08, 50.20,54.46, 63.43, 114.05, 119.10, 126.14, 126.49, 130.54, 131.70, 134.46,136.98, 139.73, 142.33, 148.32, 152.16, 152.94. ES-MS m/z 439 (M+H);Anal. Calcd. for (C₂₇H₃₀N₆×3.2 HBr×0.6 H₂O×0.6 HOAc): C, 45.51; H, 4.98;N, 11.29; Br 34.35. Found: C, 45.28; H, 5.13; N, 11.14; Br, 34.32.

EXAMPLE: 57

[0429]

AMD9685: Preparation of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-8-quinolin-8-yl)-amino]-methyl}-benzaldehydeoxime

[0430] To a stirred solution ofN′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(200 mg, 0.50 mmol) in MeOH (5 mL) was added solid sodium tungstatedihydrate (332 mg, 1.0 mmol) followed by a 35 wt % aqueous solution ofhydrogen peroxide (2.9 mL, 30 mmol). The resulting suspension wasstirred 3 h, then saturated aqueous sodium bicarbonate (5 mL) was added.The phases were separated and the aqueous layer was extracted withCH₂Cl₂ (3×10 mL), then the combined organic extracts were washed oncewith brine (10 mL), dried (MgSO₄), and concentrated in vacuo.Purification of the crude material by flash chromatography (silica gel,75:1:1 CH-₂Cl_(2/)MeOH/NH₄OH) afforded the title compound (130 mg, 63%)as a white solid. ¹H NMR (CDCl₃) δ1.63-1.66 (m, 1H), 1.97-2.07 (m, 2H),2.25-2.27 (m, 1H), 2.66-2.72 (m, 1H), 2.80-2.85 (m, 1H), 3.65 (d, 1H,J=14 Hz), 3.71 (d, 1H, J=14 Hz), 5.03 (d, 1H, J=16 Hz), 4.14 (dd, 1H,J=9, 7 Hz), 4.21 (d, 1H, J=16 Hz), 7.11-7.19 (m, 3H), 7.41-7.48 (m, 6H),7.65 (br d, 1H, J5 Hz), 8.18 (s, 1H), 8.67 (dd, 1H, J=5,1 Hz); ¹³C NMR(CDCl₃) δ22.2, 23.9, 30.2, 49.5, 55.0, 61.2, 112.1, 119.4, 122.7, 123.3,127.8, 130.1, 133.0, 136.2, 138.7, 141.4, 147.8, 150.0, 156.2, 157.7.ES-MS m/z 412 (M+H). Anal. Calcd. for C₂₅H₂₅N₅O.0.4H₂O.0.3CH₂Cl₂: C,68.41; H, 5.99; N, 15.77. Found: C, 68.57; H 5.86; N, 15.48.

EXAMPLE: 58

[0431]

AMD9773: Preparation of[4-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-aminomethyl]-benzamidine(hydrobromide salt)

[0432] Using General Procedure B: To a solution of 4-cyanobenzaldehyde(0.15 g, 1.1 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.38 g, 1.0 mmol) in CH₂Cl₂ (10 mL) was added NaBH(OAc)₃ (0.36 g, 1.7mmol) and the mixture stirred at room temperature for 6 h. Purificationof the crude material by column chromatography on silica gel (2%MeOH/CH₂Cl₂) afforded the N-alkylated product (0.26 g, 72%) as a whitesolid. ¹H NMR (CDCl₃) δ1.74 (s, 10H), 1.95 (m, 1H), 2.02 (m, 1H), 2.30(m, 1H), 2.75 (m, 2H), 3.80 (d, 1H, J=15.0 Hz), 3.97 (d, 1H, J=15.0 Hz),4.31 (m, 1H), 4.65 (d, 1H, J=12.0 Hz), 4.75 (d, 1H, J=12.0 Hz), 7.04 (m,1H), 7.16 (d, 1H, J=7.2 Hz), 7.22-7.30 (m, 5H), 7.51 (m, 1H), 7.61 (m,1H), 8.45 (d, 1H, J=3.5 Hz).

[0433] To a solution of the material from above (0.26 g, 0.53 mmol) inanhydrous EtOH (3.5 mL) at 0° C. was bubbled HCl gas for 30 min and themixture stirred at room temperature for an additional 4 h. The reactionwas concentrated under reduced pressure and the resultant residue washedwith diethyl ether (3×20 mL) and dried in vacuo to afford the desiredethoxyimine HCl salt which was used immediately in the next reaction. ¹HNMR (D₂O) δ1.54 (t, 3H, J=6.9 Hz), 1.91 (m, 1H), 2.23 (m, 2H), 2.47 (m,1H), 3.04 (m, 2H), 3.88 (d, 1H, J=12.9 Hz), 3.96 (d, 1H, J=13.2 Hz),4.44 (d, 1H, J=15.6 Hz), 4.46 (q, 2H, J=6.9 Hz), 4.63 (d, 1H, J=16.5Hz), 4.78 (m, 1H), 7.35 (d, 2H, J=8.4 Hz), 7.47-7.58 (m, 5H), 7.95 (t,1H, J=6.2 Hz), 8.41 (d, 1H, J=6.2 Hz), 8.82 (d, 1H, J=3.5 Hz).

[0434] To a solution of(N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(4-ethoxyiminebenzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-aminehydrochloride salt (from above) in anhydrous EtOH (3 mL) was addedammonium carbonate (0.24 g, 2.5 mmol) and the solution stirred at roomtemperature for 16 h. The reaction was concentrated under reducedpressure and purified by chromatography through a plug of silica gel(MeOH/NH₄OH/CH₂Cl₂, 15:10:75) to give the desired benzamidine (0.10 g,48% yield over 2 steps) as a white powder. ¹H NMR (CDCl₃) 5 1.68 (m,1H), 2.03 (m, 2H), 2.27 (m, 1H), 2.78 (m, 2H), 3.78 (s, 2H), 3.92 (d,1H, J=15.0 Hz), 4.09 (m, 1H), 4.20 (d, 1H, J=15.0 Hz), 5.68 (br, 1H),6.12 (br, 1H), 7.18 (m, 3H), 7.46 (m, 3H), 7.57 (m, 2H), 7.65 (d, 2H,J=7.2 Hz), 8.71 (d, 1H, J=3.5 Hz).

[0435] Using General Procedure D: Conversion of the material from above(100 mg) to the hydrobromide salt provided AMD9773 (70 mg) as a whitesolid. ¹H NMR (D₂O) δ1.88 (br m, 1H), 2.25 (m, 2H), 2.45 (br m, 1H),3.03 (br m, 2H), 3.88 (d, 1H, J=12.9 Hz) 3.95 (d, 1H, J=12.9 Hz), 4.45(d, 1H, J=16.2 Hz), 4.63 (d, 1H, J=16.2 Hz), 4.79 (m, 1H), 7.36 (s, 4H),7.47 (dd, 2H, J=3.0, 6.3 Hz), 7.58 (dd, 2H, J=3.0, 6.3 Hz), 7.93 (t, 1H,J=6.9 Hz), 8.40 (d, 1H, J=8.1 Hz), 8.77 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O)δ20.43, 21.00, 27.87, 50.12, 56.72, 63.21, 113.97 (2C), 126.17, 126.67,126.87 (2C), 127.56 (2C), 130.61, 130.85 (2C), 139.85, 141.09, 143.36(2C), 148.27, 150.71, 151.44, 165.18. ES-MS m/z 411 (M+H). Anal. Calcd.for C₂₅H₂₆N₆.2.9HBr.2.0H₂O: C, 43.89; H, 4.85; N, 12.28; Br 34.34.Found: C, 43.97; H, 4.90; N, 12.02; Br, 34.35.

EXAMPLE: 59

[0436]

AMD9717: Preparation of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl alcohol

[0437] To a stirred solution of 8-amino-5,6,7,8-tetrahydroquinoline(5.56 g, 37.5 mmol) in dry MeOH (150 mL) was added4-hydroxymethylbenzaldehyde (7.22 g, 52.5 mmol) under an argonatmosphere and the mixture was stirred overnight at room temperature. Tothe resultant solution was added sodium borohydride (2.85 g, 75 mmol) inthree portions over 45 minutes and the reaction mixture stirred for 24 hto afford a pale yellow oil which was used in the next step without anyfurther purification (see General Procedure B).

[0438] To a stirred solution of the oil from above (7.64 g) in dry CH₃CN(100 mL) was added N,N-diisopropylethylamine (10 mL, 57 mmol), potassiumiodide (0.24 g, 1.4 mmol) and1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole (7.98 g, 29.9 mmol)as a solution in CH₃CN (50 mL). The mixture was stirred under an argonatmosphere at 60° C. overnight. The reaction mixture was concentrated invacuo, diluted with CH₂Cl₂ (100 mL) and washed with saturated aqueousammonium chloride (150 mL). The aqueous layer was extracted with CH₂Cl₂(2×50 mL) and the combined organic layers were dried (Na₂SO₄), filtered,and concentrated in vacuo. A solution of the crude material from abovein CH₂Cl₂/trifluoroacetic acid (2:1, 30 mL) was stirred for 3 h at roomtemperature. The reaction mixture was diluted with CH₂Cl₂ (30 mL) andconcentrated in vacuo. The residue was diluted with CH₂Cl₂ (50 mL) andwashed with 1N NaOH (50 mL). The aqueous layer was extracted with CH₂Cl₂(2×30 mL) and the combined organic layers were dried (Na₂SO₄), filtered,and concentrated in vacuo to afford a brown foam. A small portion (111mg) of the crude material was purified by radial chromatography on a 1mm TLC grade silica gel plate (CH₂Cl₂/MeOH/NH₄OH, 100:1:1) to afford thefree base, AMD9717, (31.4 mg, 28%) as a white foam. ¹H NMR (CDCl₃)δ1.68-1.77 (br m, 1H), 1.97-2.08 (m, 2H), 2.24-2.28 (m, 1H), 2.70-2.91(m, 2H), 3.75 (s, 2H), 3.95 (d, 1H, J=16.8 Hz), 4.09 (m, 1H), 4.17 (d,1H, J=16.8 Hz), 4.59 (s, 2H), 7.14-7.24 (m, 6H), 7.38-7.45 (m, 3H),7.49-7.51 (m, 1H), 7.61-7.65 (m, 1H), 8.70 (d, 1H, J=4.8 Hz); ¹³C NMR(CDCl₃) δ20.24, 21.78, 28.17, 47.73, 52.85, 59.21, 63.41, 120.42,121.11, 125.75, 127.78, 133.84, 136.27, 137.16, 139.22, 145.76, 154.60,156.10; ES-MS m/z 399 (M+H); Anal. Calcd. forC₂₅H₂₆N₄O.0.3CH₂Cl₂.0.25H₂O: C, 70.92; H, 6.37; N, 13.08. Found: C,71.25; H, 6.53; N, 12.68.

EXAMPLE: 60

[0439]

AMD9882: Preparation of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde

[0440] To a stirred solution of the alcohol from above,4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzylalcohol (AMD9717), (9.29 g) in dry CH₂Cl₂ (200 mL) was added MnO₂ (20.3g, 233 mmol) and the mixture stirred for 4 h at room temperature. Anadditional portion of MnO2 (8.5 g, 97.8 mmol) was then added and themixture stirred overnight at room temperature. The reaction mixture wasfiltered through a celite pad, the cake washed with CHCl₃ and theresultant filtrate concentrated in vacuo. Purification of the crudeproduct by column chromatography on silica gel (CH₂Cl₂/MeOH, 97:3followed by 96:4) afforded the aldehyde (5.08 g, 34%, 5 steps) as a paleyellow solid. ¹H NMR (CDCl₃) δ1.56-1.74 (br m, 2H), 1.92-2.09 (m, 2H),2.28-2.32 (m, 1H), 2.70-2.94 (m, 2H), 3.84 (s, 2H), 3.94 (d, 1H, J=16.5Hz), 4.08-4.14 (m, 1H), 4.23 (d, 1H, J=16.5 Hz), 7.18-7.26 (m, 4H), 7.45(d, 1H, J=7.8 Hz), 7.56 (m, 4H), 7.76 (d, 2H, J=8.1 Hz), 8.72 (d, 1H,J=4.2 Hz), 9.92 (s, 1H). ¹³C NMR (CDCl₃) δ21.29, 23.73, 29.11, 48.90,53.90, 60.56, 121.85 (2 carbons), 122.53 (2 carbons), 129.04 (2carbons), 129.86 (2 carbons), 134.89, 135.58, 137.57 (2 carbons),146.69, 146.85, 155.58, 156.99, 191.85. ES-MS m/z 397 (M+H). Anal.Calcd. for C₂₅H₃₄N₄O.0.15CH₂Cl₂: C, 73.82; H, 5.98; N, 13.69. Found: C,73.69; H, 6.16; N, 13.78.

EXAMPLE: 61

[0441]

AMD971 1: Preparation of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid methyl ester

[0442] Following General Procedure B: To a solution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(680 mg, 1.8 mmol) and methyl 4-formylbenzoate (295 mg, 1.8 mmol) inCH₂Cl₂ (10 mL) was added NaBH(OAc)₃ (763 mg, 3.6 mmol) and the mixturestirred for 18 h. The resulting crude material was taken up in neat TFA(2 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (10 mL) wascautiously added, and the resulting mixture was extracted with CH₂Cl₂(3×20 mL), and the combined organic extracts were dried (MgSO₄), andconcentrated in vacuo. Purification of the crude material by flashchromatography (silica gel, 50:2:1 CH₂Cl₂/MeOH/NH₄OH) afforded the titlecompound (565 mg, 74%) as a white solid. ¹H NMR (CDCl₃) δ1.64-1.75 (m,1H), 2.01-2.08 (m, 2H), 2.26-2.28 (m, 1H), 2.74-2.76 (m, 1H), 2.81-2.86(m, 1H), 3.81 (s, 2H), 3.86 (s, 3H), 3.94 (d, 1H, J=17 Hz), 4.09 (dd,11H, J=9, 7 Hz), 4.21 (d, 1H, J=17 Hz), 7.18-7.22 (m, 3H), 7.44 (br d,1H, J=8 Hz), 7.49 (d, 2H, J=8 Hz), 7.50-7.53 (m, 11H), 7.64-7.66 (m,1H), 7.91 (d, 2H, J=8 Hz), 8.70 (dd, 1H, J=5, 1 Hz); ¹³C NMR (CDCl₃)δ21.2, 23.6, 29.0, 48.7, 51.9, 53.7, 111.0, 118.6, 121.5, 122.3, 129.3,128.9, 129.5, 134.7, 137.2, 144.8, 146.8, 155.7, 157.1, 166.8. ES-MS m/z427 (M+H). Anal. Calcd. for C₂₆H₂₆N₄O₂.0.6H₂O.0.3CH₂Cl₂: C, 68.26; H,6.05; N, 12.11. Found: C, 68.57; H, 6.12; N, 11.75.

EXAMPLE: 62

[0443]

AMD9738: Preparation of(R,S)-4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-N-hydroxy-benzamide

[0444] To a stirred solution of4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid methyl ester (AMD9711) (120 mg, 0.23 mmol) in dry MeOH (3 mL) wasadded hydroxylamine hydrochloride (32 mg, 0.46 mmol) followed bypotassium hydroxide (39 mg, 0.69 mmol). The resulting solution wasstirred for 18 h, at which point water (5 mL) and CH₂Cl₂ (5 mL) wereadded. The phases were separated and the aqueous layer was adjusted topH 7 by the addition of saturated aqueous ammonium hydroxide, thenextracted with CH₂Cl₂ (3×10 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated in vacuo. Purification of thecrude material by radial chromatography (1 mm plate, 10:1:1CH₂Cl₂/MeOH/NH₄OH) afforded the title compound (52 mg, 43%) as a whitesolid. ¹H NMR (CDCl₃) δ1.58-1.61 (m, 1H), 1.87-1.91 (m, 2H), 2.12-2.14(m, 1H), 2.61-2.66 (m, 1H), 2.73-2.77 (m, 1H), 3.55 (br s, 2H), 3.79 (brd, 1H, J=16 Hz), 3.98-4.00 (m, 1H), 4.09 (br d, 1H, J=16 Hz), 7.08-7.11(m, 3H), 7.23-7.26 (m, 2H), 7.38 (br d, 1H, J=8 Hz), 7.48-7.51 (m, 4H),8.60 (br d, 1H, J=4 Hz); ³C NMR (CDCl₃) δ21.2, 23.1, 29.1, 48.6, 53.9,60.5, 121.9, 122.4, 127.0, 128.8, 130.7, 135.1, 137.7, 142.9, 146.7,155.2, 156.7, 166.3. ES-MS m/z 428 (M+H). Anal. Calcd. forC₂₅H₂₅N₅O.0.8CH₂Cl₂: C, 64.63; H, 5.59; N, 14.61. Found: C, 64.94; H,5.69; N, 14.23.

EXAMPLE: 63

[0445]

AMD9743: Preparation of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid hydrazide

[0446] To a stirred solution of4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid methyl ester (AMD9711) (140 mg, 0.33 mmol) in dry ethanol (3 mL)was added hydrazine monohydrate (0.5 mL, 10.3 mmol) and the resultingmixture was heated at 80° C. for 24 h. Saturated aqueous sodiumbicarbonate (5 mL) was added, the phases separated and the aqueous layerextracted with CH₂Cl₂ (3×10 mL). The combined organic extracts weredried (MgSO₄) and concentrated in vacuo. Purification of the crudematerial by radial chromatography (1 mm plate, 75:1:1 CH₂Cl₂-MeOH-NH₄OH)afforded the title compound (89 mg, 61%) as a white solid. ¹H NMR(CDCl₃) δ1.64-1.68 (m, 1H), 1.94-2.04 (m, 2H), 2.20-2.24 (m, 1H),2.66-2.72 (m, 1H), 2.78-2.83 (m, 1H), 3.73 (s, 2H), 3.93 (d, 1H, J=16Hz), 4.00-4.12 (m, 3H), 4.15 (d, 1H, J=16 Hz), 7.14-7.18 (m, 3H), 7.40(d, 2H, J=8 Hz), 7.50 (br d, 1H, J=7 Hz), 7.58 (d, 2H, J=8 Hz), 7.62 (brd, 1H, J=7 Hz), 8.06 (s, 1H), 8.66 (dd, 1H, J=5, 1 Hz); ¹³C NMR (CDCl₃)δ21.2, 23.6, 29.0, 48.7, 53.7, 60.4, 111.4, 118.4, 121.5, 122.3, 126.9,128.6, 131.5, 134.7, 137.3, 143.5, 146.8, 155.8, 157.1, 168.4. ES-MS m/z427 (M+H). Anal. Calcd. for C₂₅H₂₆N₆O.0.5CH₂Cl₂: C, 65.31; H, 5.80; N,17.92. Found: C, 65.22; H, 5.77; N, 17.97.

EXAMPLE: 64

[0447]

AMD9769: Preparation of4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid (hydrobromide salt)

[0448] To a solution of the4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid methyl ester (AMD9711) (90 mg, 0.21 mmol) in MeOH (2.5 mL) wasadded aqueous NaOH (3.5 m, 0.30 mL, 1.05 mmol). The reaction mixture washeated at 40° C. for 16 h after which the solution was concentrated,washed with saturated aqueous NaHCO₃ (10 mL) and extracted with CH₂Cl₂(2×50 mL). The aqueous layer was acidified to pH 4 with 10% aqueous HCl,saturated with NaCl(s) and the product was extracted with CH₂Cl₂ (3×75mL). The combined organic extracts were dried over MgSO₄ andconcentrated to a light yellow foam. ¹H NMR (300 MHz, CDCl₃) δ8.71 (d,1H, J=5.8 Hz), 7.84 (d, 2H, J=8.1 Hz), 7.62 (br s, 2H), 7.52 (d, 1H,J=8.1 Hz), 7.35 (d, 2H, J=8.1 Hz), 7.23-7.17 (m, 3H), 4.29-4.21 (m, 2H),3.95 (d, 1H, J=16.2 Hz), 3.74 (s, 2H), 2.95-2.86 (m, 1H), 2.79-2.74 (m,1H), 2.37-2.25 (m, 1H), 2.18-2.11 (m, 2H), 1.83-1.74 (m, 1H).

[0449] Following General Procedure D: Conversion of the foam from aboveto the hydrobromide salt gave AMD9769. ¹H NMR (300 MHz, D₂0) δ8.77 (d,1H, J=6.0 Hz), 8.41 (d, 1H, J=7.8 Hz), 7.94 (dd, 1H, J=7.5, 5.7 Hz),7.53-7.42 (m, 6H), 7.22-7.19 (m, 2H), 4.78-4.73 (m, 1H), 4.62 (d, 1H,J=16.2 Hz), 4.43 (d, 1H, J=16.2 Hz), 3.87 (d, 1H, J=12.9 Hz), 3.78 (d,1H, J=12.9 Hz), 3.05-3.03 (m, 2H), 2.47-2.43 (m, 1H), 2.32-2.21 (m, 2H),1.93-1.87 (m, 1H); ¹³C NMR (75.5 MHz, D₂O) δ172.1, 153.5, 152.9, 150.4,144.2, 143.2, 141.8, 132.6, 132.3, 131.7, 131.2, 128.9, 128.3, 115.9,65.6, 58.9, 52.4, 30.0, 23.1, 22.5. ES-MS m/z 413.2 (M+H). Anal Calcdfor (C₂₅H₂₄N₄O₂).2(HBr).1.3(H2O): C, 50.24; H, 4.82; N, 9.37; Br, 26.74.Found: C, 50.58; H, 4.96; N, 9.00; Br, 26.35.

EXAMPLE: 65

[0450]

AMD9770: Preparation of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzamide

[0451] Preparation of 4-Formylbenzamide

[0452] Neat thionyl chloride (1.94 mL, 27 mmol) was added dropwise to astirred suspension of 4-formylbenzoic acid (2.0 g, 13 mmol) in dryCH₂Cl₂ (50 mL). The resulting slurry was stirred 18 h, at which time thesolvent and excess thionyl chloride was removed in vacuo. The residualsolid was redissolved in dry THF (50 mL) and ammonia gas was bubbledthrough the solution for 15 min, which resulted in the formation of awhite precipitate. The mixture was poured into saturated aqueous sodiumbicarbonate (30 mL) and chloroform (100 mL) was added. The phases wereseparated and the aqueous layer was extracted with CHCl₃ (3×30 mL). Thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo. Purification of the crude material by flash chromatography onsilica gel (20:1:1 CH₂Cl₂-MeOH-NH₄OH) afforded the title compound (85mg, 4%) as a white solid. ¹H NMR (CDCl₃) δ5.96 (br s, 1H), 6.19 (br 2,1H), 7.97 (s, 4H), 10.09 (s, 1H).

[0453] Following the General Procedure B: To a solution of(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(216 mg, 0.57 mmol) and 4-formylbenzamide (85 mg, 0.57 mmol) in CH₂Cl₂(5 mL) was added sodium triacetoxyborohydride (242 mg, 1.14 mmol) andthe reaction stirred for 18 h. The resultant crude material was taken upin neat TFA (2 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate(10 mL) was cautiously added, and the resulting mixture was extractedwith CH₂Cl₂ (3×20 mL) then the combined organic extracts were dried(MgSO₄), filtered and concentrated in vacuo. Purification of the crudematerial by radial chromatography on silica gel (1 mm plate, 50:1:1CH₂Cl₂-MeOH-N₄OH) afforded the title compound (66 mg, 28%) as a whitesolid. ¹H NMR (CDCl₃) δ1.67-1.73 (m, 1H), 2.00-2.08 (m, 2H), 2.26-2.30(m, 1H), 2.71-2.76 (m, 1H), 2.82-2.87 (m, 1H), 3.80 (s, 2H), 3.92 (d,1H, J=16 Hz), 4.09 (dd, 1H, J=9, 7 Hz), 4.20 (d, 1H, J=16 Hz), 5.56 (brs, 1H), 6.01 (br s, 1H), 7.17-7.22 (m, 3H), 7.43-7.53 (m, 4H), 7.65-7.67(m, 3H), 8.70 (dd, 1H, J=5, 1 Hz); ¹³C NMR (CDCl₃) δ21.3, 23.7, 29.1,48.7, 53.7, 60.5, 121.7, 122.4, 127.4, 128.7, 132.3, 134.8, 137.4,143.8, 146.9, 155.8, 157.1, 169.1. ES-MS m/z 412 (M+H). Anal. Calcd. forC₂₅H₂₅N₅O.1.45H₂O.0.6CH₂Cl₂: C, 63.84; H, 6.34; N, 13.76. Found: C,64.03; H, 5.95; N, 13.37.

EXAMPLE: 66

[0454]

AMD11130: Preparation of(6-Amino-pyridin-2-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0455] Using the general N-alkylation procedure: To a stirred solutionof N-[6-(bromomethyl)-2-pyridyl]pivalamide (prepared as described byHarata, M.; Hasegawa, K.; Jitsukawa, K.; Masuda, H.; Einaga, H. Bull.Chem. Soc. Jpn 1998, 71, 1031-1038) (0.129 g, 0.45 mmol) in dry CH₃CN(10 mL) was added(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.176 g, 0.47 mmol), N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) andpotassium iodide (12 mg, 0.048 mmol). The mixture was stirred under anargon atmosphere at 60° C. for 3.75 h. Purification of the crudematerial by column chromatography on silica gel (CH₂Cl₂/MeOH, 98:2followed by 96:4) gave the alkylated product (0.148 g, 54%) as a brownoil.

[0456] Using General Procedure D: Conversion of the amine from above (43mg, 0.074 mmol) to the hydrobromide salt with simultaneous removal ofthe Boc groups gave AMD11130 (41 mg, 84%) as a yellow solid. ¹H NMR(D₂O) δ1.86-1.92 (m, 1H), 2.15-2.26 (m, 2H), 2.40-2.45 (m, 1H),3.00-3.01 (m, 2H), 3.99 (d, 1H, J=14.4 Hz), 4.15 (d, 1H, J=14.7 Hz),4.36 (d, 1H, J=15.9 Hz), 4.52 (d, 1H, J=15.9 Hz), 4.76-4.79 (m, 1H,overlap with HOD), 6.45 (d, 1H, J=9 Hz), 6.70 (d, 1H, J=6.9 Hz), 7.43(dd, 1H, J=9, 7.5 Hz), 7.57 (dd, 2H, J=6.3, 3 Hz), 7.67 (dd, 2H, J=6.3,3 Hz), 7.89 (dd, 1H, J=7.8, 6 Hz), 8.37 (d, 1H, J=7.5 Hz), 8.74 (d, 1H,J=5.7 Hz); ¹³C NMR (D₂O) δ20.30, 20.86 27.81, 48.12, 54.65, 62.49,113.24, 113.78, 114.19, 126.26, 127.22, 127.36, 130.88, 140.30, 141.10,143.85, 144.14, 148.38, 149.38, 149.63; ES-MS m/z 385 (M+H); Anal.Calcd. for C₂₃H₂₄N₆.3.0HBr.1.8H₂O: C, 41.88; H, 4.68; N, 12.74; Br,36.34. Found: C, 41.85; H, 4.61; N, 12.45; Br, 36.44.

EXAMPLE: 67

[0457]

AMD 11157: Preparation of(2-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol(free base).

[0458] Using general procedure B {direct reductive amination usingNaBH(OAc)₃}: Reaction of phthalic dicarboxaldehyde (0.139 g, 1.04 mmol)and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.183 g, 0.48 mmol) with NaBH(OAc)₃ (0.504 g, 2.38 mmol) in CH₂Cl₂ (5mL) for 20 hours followed by purification of the crude material byradial chromatography on silica gel (2 mm plate, 100:1 CH₂Cl₂-CH₃OH)provided 0.108 g (45%) of a white foam. The foam (0.108 g, 0.22 mmol)was dissolved in CH₂Cl₂ (2 mL) and treated with trifluoroacetic acid (1mL). The resultant solution was stirred at room temperature for 90minutes then concentrated under reduced pressure. The residue wasdissolved in CH₂Cl₂ (10 mL) and NaOH (1.0 M, ˜10 mL) so that the aqueousphase was basic (pH 14). The phases were separated and the aqueous phasewas extracted with CH₂Cl₂ (3×10 mL). The combined organic extracts weredried (Na₂SO₄) and concentrated. Purification of the crude material byradial chromatography on silica gel (1 mm plate, 100:1:1CH₂Cl₂-CH₃OH-NH₄OH) provided 0.079 g (91%) of AMD 11157 as a whitesolid.

[0459]¹H NMR (CDCl₃) δ1.61-1.76 (m, 2H), 1.89-2.02 (m, 1H), 2.07-2.13(m, 1H), 2.33-2.40 (m, 1H), 2.69-2.90 (m, 2H), 3.81 (d, 1H, J=15.0 Hz),3.82 (d, 1H, J=12.6 Hz), 3.95 (d, 1H, J=15.0 Hz), 3.98 (t, 1H, J=8.1Hz), 4.06 (d, 1H, J=12.6 Hz), 4.50 (d, 1H, J=11.7 Hz), 4.63 (d, 1H,J=11.7 Hz), 7.06-7.21 (m, 6H), 7.38-7.46 (m, 3H), 7.62 (br s, 1H), 8.09(br s, 1H), 8.44 (br d, 1H, J=4.2 Hz); ¹³C NMR (CDCl₃) δ20.90, 21.40,29.0 49.28, 55.26, 60.09, 62.90, 111.04, 118.81, 121.48, 122.23, 127.93,128.50, 130.95, 131.83, 134.83, 137.27, 137.63, 140.38, 146.78, 153.60,156.28. ES-MS m/z 399 (M+H). Anal. Calcd. for C₂₅H₂₆N₄O.1.0H₂O: C,72.09; H, 6.78; N, 13.45. Found: C, 72.15; H, 6.43; N, 13.29.

EXAMPLE: 68

[0460]

AMD11156: Preparation ofO-(2-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-hydroxylamine(hydrobromide salt)

[0461] Preparation of 2-(2-Bromomethyl-benzyloxy)-isoindole-1,3-dione

[0462] To a stirred solution of N-hydroxyphthalimide (0.60 g, 3.68 mmol)and Et₃N (0.60 mL, 4.30 mmol) in DMF (6 mL) was addedα,α′-dibromo-o-xylene (3.30 g, 0.0125 mol) and the mixture stirred atroom temperature for 4 h. The resultant brown precipitate was filteredand washed with CH₂Cl₂. The filtrate was diluted with EtOAc (40 mL) andwater (30 mL) and the organic phase washed with brine (1×30 mL), dried(Na₂SO₄) and concentrated under reduced pressure. The resultant yellowoil was purified by column chromatography on silica gel (4:1Hexanes/EtOAc) to give the title compound (581 mg, 46%) as a whitesolid. ¹H NMR (CDCl₃) δ4.99 (s, 2H), 5.37 (s, 2H), 7.27-7.40 (m, 2H),7.41-7.45 (m, 2H), 7.73-7.76 (m, 2H), 7.81-7.84 (m, 2H).

[0463] Using the general alkylation procedure: To a stirred solution of2-(2-bromomethyl-benzyloxy)-isoindole-1,3-dione (0.308 g, 0.89 mmol) indry CH₃CN (10 mL) was added(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.274 g, 0.725 mmol), N,N-diisopropylethylamine (0.21 mL, 1.21 mmol)and potassium iodide (12 mg, 0.048 mmol). The mixture was stirred underan argon atmosphere at 60° C. for 2.75 h. Purification of the crudematerial by column chromatography on silica gel (CH₂Cl₂/MeOH, 98:2followed by 96:4) gave the alkylated product (0.32 g, 69%) as a whitefoam.

[0464] To a solution of the foam from above (219 mg, 0.34 mmol) in EtOH(96%, 5 mL) was added hydrazine monohydrate (0.10 mL, 2 mmol) and thesolution stirred at room temperature for 3 days. The mixture wasfiltered (to remove the resultant white solid) and washed with CH₂Cl₂.The filtrate was concentrated under reduced pressure and purified byradial chromatography on silica gel (1mm plate, CH₂Cl₂/MeOH/NH₄OH,100:1:1) to give the desired deprotected amine (44 mg, 31%) as a whitefoam.

[0465] Using General Procedure D: Conversion of the amine from above (39mg, 0.094 mmol) to the hydrobromide salt gave AMD11156 (59 mg, 90%) as awhite solid. ¹H NMR (D₂O) δ1.88-1.93 (m, 1H), 2.19-2.32 (m, 2H),2.45-2.49 (m, 1H), 3.03-3.04 (m, 2H), 3.85 (d, 1H, J=13.5 Hz), 4.17 (d,1H, J=13.5 Hz), 4.36 (d, 1H, J=16.2 Hz), 4.55 (d, 1H, J=16.2 Hz),4.76-4.79 (m, 1H, overlap with HOD), 5.10 (d, 1H, J=10.8 Hz), 5.24 (d,1H, J=10.8 Hz), 6.91 (t, 1H, J=7.5 Hz), 7.07 (d, 1H, J=6.9 Hz), 7.14 (t,1H, J=7.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.51 (dd, 2H, J=6.3, 3 Hz), 7.58(dd, 2H, J=6.3, 3 Hz), 7.90 (dd, 1H), J=7.8, 6 Hz), 8.38 (d, 1H, J=7.5Hz), 8.73 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ20.42, 20.80, 27.88, 48.98,52.84, 62.08, 74.83, 113.93, 126.16, 126.81, 128.85, 130.56, 131.21,131.52, 131.87, 136.51, 139.88, 141.13, 148.36, 150.49, 150.80; ES-MSm/z 414 (M+H); Anal. Calcd. for C₂₅H₂₇N₅O.3.0HBr.2.2H₂O: C, 43.15; H,4.98; N, 10.06; Br, 34.45. Found: C, 43.37; H, 5.05; N, 9.87; Br, 34.33.

EXAMPLE: 69

[0466]

AMD11191: Preparation of(4-Amino-pyridin-3-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0467] Using General Procedure B: To a stirred solution of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(252 mg, 0.91 mmol) and (3-Formyl-pyridin-4-yl)-carbamic acid tert-butylester (prepared as described by Venuti, M. C.; Stephenson, R. A. et al.J Med. Chem. 1988, 31, 2136-2145) (206 mg, 0.93 mmol) in CH₂Cl₂ (9 mL)was added NaBH(OAc)₃ (243 mg, 1.15 mmol) and the resultant mixture wasstirred at room temperature for 16 hours. A solution of the resultantcrude yellow foam (0.30 g) in 5 N HCl/THF (1:1, 6 mL) was stirred for 3days. The mixture was diluted with water (10 mL) and CH₂Cl₂ (25 mL) andmade alkaline (pH>10) with 10 N NaOH (10 mL). The layers were separatedand the aqueous phase was washed with CH₂Cl₂ (3×10 mL). The combinedorganic extracts were dried (Na₂SO₄), concentrated under reducedpressure and purified by radial chromatography on silica gel (2 mmplate, CH₂Cl₂/MeOH/NH₄OH, 100:1:1 then 50:1:1 then 20:1:1) to give thefree amine (100 mg, 29% over 2 steps) as a clear oil.

[0468] Using General Procedure D: Conversion of the amine from above (73mg, 0.19 mmol) to the hydrobromide salt gave AMD11191 (120 mg, 90%) as awhite solid. ¹H NMR (D₂O) δ1.87-1.91 (m, 1H), 2.15-2.26 (m, 2H),2.45-2.50 (m, 1H), 3.00-3.02 (m, 2H), 4.02 (d, 1H, J=14.1 Hz), 4.13 (d,1H, J=14.1 Hz), 4.34 (d, 1H, J=16.2 Hz), 4.45 (d, 1H, J=16.2 Hz),4.76-4.79 (m, 1H, overlap with HOD), 6.40 (d, 1H, J=6.9 Hz), 7.38 (d,1H, J=6.9 Hz), 7.56 (dd, 2H, J=6.3, 3 Hz), 7.66 (dd, 2H, J=6.3, 3 Hz),7.89 (dd, 1H, J=7.8, 6 Hz), 8.08 (s, 1H), 8.35 (d, 1H, J=7.8 Hz), 8.74(d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ20.41 (2 carbons), 27.92, 48.03,51.51, 61.78, 109.58, 114.04, 115.89, 126.30, 127.34, 130.58, 138.61,140.26, 140.69, 141.07, 148.25, 149.82, 150.33, 158.82; ES-MS m/z 385(M+H); Anal. Calcd. for C₂₃H₂₄N₆.3.1HBr.1.8H₂O.0.5C₄H₁₀O: C, 42.60; H,5.11; N, 11.92; Br, 35.15. Found: C, 42.91; H, 5.01; N, 11.88; Br,34.76.

EXAMPLE: 70

[0469]

AMD11065: Preparation of2-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-5-cyano-benzoicacid methyl ester

[0470] Preparation of 2-methyl-5-nitro-benzoic acid methyl ester

[0471] A solution of 2-methyl-5-nitrobenzoic acid (1.91 g, 10.6 mmol)and H₂SO₄ (catalytic) in MeOH (25 mL) was heated at reflux for 16 h,then concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (50 mL),washed with saturated NaHCO₃(aq) (2×40 mL), then dried (MgSO₄),filtered, and concentrated in vacuo to give yellow crystals (1.50 g,73%). ¹H NMR (CDCl₃) δ2.72 (s, 3H), 3.96 (s, 3H), 7.44 (d, 1H, J=9.0Hz), 8.24 (dd, 1H, J=9.0,3.0 Hz), 8.78 (d, 1H, J=3.0 Hz).

[0472] Preparation of 5-Amino-2-methyl-benzoic acid methyl ester:NH₂

[0473] A solution of 2-methyl-5-nitro-benzoic acid methyl ester (1.50 g,7.8 mmol) in 4:1 MeOH/EtOAc (20 mL) was shaken at room temperature witha suspension of 10% Pd/C (175 mg, 0.17 mmol) under hydrogen atmosphere(35 psi) for 17 h. The catalyst was removed by filtration over celite,and the filtrate was concentrated in vacuo to give a pale yellow oil(1.29 g, 99%). ¹H NMR (CDCl₃) δ2.46 (s, 3H), 3.63 (br s, 2H), 3.87 (s,3H), 6.74 (dd, 1H, J=9.0, 3.0 Hz), 7.02 (d, 1H, J=6.0 Hz), 7.25 (d, 1H,J=3.0 Hz).

[0474] Preparation of 5-Cyano-2-methyl-benzoic acid methyl ester

[0475] To a stirred suspension of 5-amino-2-methyl-benzoic acid methylester (1.29 g, 7.80 mmol) in H₂O (2.0 mL) was slowly added conc. HCl(2.0 mL) at room temperature. More H₂O (15 mL) was added, and themixture was stirred at 0° C. while a solution of NaNO₂ (592 mg, 8.58mmol) in H₂O (2.2 mL) was added dropwise. After the amine had completelydissolved, K₂CO₃(s) was added slowly at 0° C. until the solution wasneutralized.

[0476] Copper(I) cyanide (838 mg, 9.36 mmol) was dissolved in a solutionof NaCN (918 mg, 18.7 mmol) in H₂O (2.9 mL), and the solution was heatedto 60° C. The cold neutralized diazonium salt solution was addeddropwise to the vigorously stirred cyanide solution at 60° C. Themixture was heated to 110° C. for 1 h then allowed to cool to roomtemperature. The mixture was diluted with saturated NaHCO₃(aq) (15 mL)and extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts weredried (MgSO₄), filtered, and concentrated in vacuo. The crude materialwas filtered through silica gel (20% EtOAc/hexanes) to give yellowcrystals (990 mg, 72%). ¹H NMR (CDCl₃) δ2.68 (s, 3H), 3.93 (s, 3H), 7.38(d, 1H, J=9.0 Hz), 7.66 (dd, 1H, J=9.0, 3.0 Hz), 8.22 (d, 1H, J=1.5 Hz).

[0477] Preparation of 2-Bromomethyl-5-cyano-benzoic acid methyl ester

[0478] A mixture of 5-cyano-2-methyl-benzoic acid methyl ester (913 mg,5.21 mmol), NBS (1.02 g, 5.73 mmol), and AIBN (128 mg, 0.780 mmol) inCCl₄ (20 mL) was heated at reflux for 24 h then allowed to cool to roomtemperature. The mixture was filtered, and the filtrate was concentratedin vacuo. Purification of the crude material by column chromatography onsilica gel (10% EtOAc/hexanes) afforded yellow crystals (720 mg, 55%).¹H NMR (CDCl₃) δ3.99 (s, 3H), 4.96 (s, 2H), 7.62 (d, 1H, J=9.0 Hz), 7.77(dd, 1H, J=9.0, 3.0 Hz), 8.27 (d, 1H, J=3.0 Hz).

[0479] A mixture of2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzoimidazole-1-carboxylicacid tert-butyl ester (762 mg, 2.01 mmol), 2-bromomethyl-5-cyano-benzoicacid methyl ester (511 mg, 2.01 mmol), potassium iodide (19 mg, 0.10mmol), and N,N-diisopropylethylamine (0.53 mL, 3.02 mmol) inacetonitrile (16 mL) was heated at 60° C. for 16 h. The reaction mixturewas concentrated in vacuo and the residue diluted with CH₂Cl₂ (25 mL)and saturated NaHCO₃(aq) (30 mL). The layers were separated and theaqueous layer was extracted with CH₂Cl₂ (2×20 mL). The combined organicextracts were dried (MgSO₄), filtered, and concentrated in vacuo.Purification of the crude material on silica gel (500:10:1CH₂Cl₂/MeOH/NH₄OH) gave a white foam (935 mg, 84%).

[0480] The purified material from above (50 mg, 0.11 mmol) was dissolvedin dry CH₂Cl₂ (1.5 mL) and trifluoroacetic acid (2.0 mL) was addeddropwise. The resultant mixture was stirred for 2.5 h at roomtemperature. The reaction mixture was diluted with CH₂Cl₂ (15 mL) andthen concentrated in vacuo to remove any excess trifluoroacetic acid.The concentrate was diluted with CH₂Cl₂ (20 mL) and 1N NaOH (20 mL). Thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(2×15 mL) and then the combined organic layers were dried (Na₂SO₄),filtered, and concentrated in vacuo to afford AMD11165 as a yellow foam.¹H NMR (CDCl₃) δ1.62-1.79 (m, 1H), 1.92-2.10 (m, 2H), 2.26-2.34 (m, 1H),2.69-2.93 (m, 2H), 3.89 (s, 3H), 3.89 (d, 1H, J=16.5 Hz), 3.95 (d, 1H,J=16.2 Hz), 4.13 (m, 1H), 4.16 (d, 1H, J=16.5 Hz), 4.57 (d, 1H, J=15.9Hz), 712-723 (m, 3H), 7.43 (d, 1H, J=7.8 Hz), 7.48 (br m, 1H), 7.58 (dd,2H, J=7.8, 1.5 Hz), 7.94 (d, 1H, J=1.8 Hz), 8.00 (d, 1H, J=8.1 Hz), 8.62(d, 1H, J=5.1 Hz). ¹³C NMR (CDCl₃) δ21.72, 24.40, 29.46, 50.21, 53.01,53.07, 111.08, 118.26, 122.28, 122.88, 130.88, 131.50, 134.05, 135.12,135.20, 137.97, 147.17, 147.26, 155.56, 157.27, 166.75. ES-MS m/z 452(M+H). Anal. Calcd. for C₂₇H₂₅N₅O₂.0.05CH₂Cl₂.0.8H₂O: C, 69.10; H, 5.72;N, 14.89. Found: C, 69.44; H, 5.87; N, 14.61.

EXAMPLE: 71

[0481]

AMD11179: Preparation of4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-3-cyano-benzamide

[0482] To 0.5 mL of Raney Nickel in water was added a solution of2-{[(2-cyano-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylicacid tert-butyl ester (0.55 g, 1 mmol) in methanol (25 mL). The solutionwas then saturated with ammonia gas for 10 minutes. The reaction vesselwas then shaken vigorously under an atmosphere of hydrogen (40 psi) for16 hours. The mixture was filtered through a celite pad and the filtrateconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (88:12 CH₂Cl₂:MeOH) to afford to give the amide(0.20 g, 36%). ¹H NMR (CDCl₃) δ1.73 (m, 1H), 2.01 (m, 2H), 2.35 (m, 1H),2.85 (m, 2H), 3.88 (t, 2H, J=15.9 Hz), 4.16 (m, 1H), 4.21 (d, 1H, J=9.6Hz), 4.26 (d, 1H, J=7.8 Hz), 5.71 (br, 1H, NH), 6.12 (br, 1H, NH), 7.19(m, 3H), 7.46 (d, 1H, J=7.8 Hz), 7.55 (br, 2H), 7.80 (d, 1H, J=8.1 Hz),7.87 (d, 1H, J=8.1 Hz), 7.96 (s, 1H), 8.64 (dd, 1H, J=4.5 Hz). ¹³C NMR(CDCl₃) δ21.71 29.44, 49.92, 53.09, 61.84, 112.81, 117.49, 122.30 (4C),122.97, 130.44 (2C), 131.98, 132.32, 133.56, 135.37, 138.05 (2C),147.13, 147.29, 155.27, 156.87, 167.82. ES-MS m/z 437 (M+H). Anal.Calcd. for C₂₆H₂₄N₆O..6CH₂Cl₂: C, 65.54; H, 5.21; N, 17.24. Found: C,65.93; H, 5.51; N, 17.44.

EXAMPLE: 72

[0483]

AMD9643: Preparation of[3-(1H-benzimidazol-2-yl)-benzyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(hydrobromide salt)

[0484] Preparation of 3-(benzimidazol-2-yl)-benzyl alcohol

[0485] A solution of isoterephthalic acid monomethyl ester (1.00 g, 5.6mmol) in thionyl chloride (12 mL) was stirred at 80° C. for 3.5 h. Thesolvent was removed under reduced pressure to afford isoterephthalicacid monomethyl ester chloride (1.06 g, 97%). ¹H NMR (CDCl₃) δ3.98 (s,3H), 7.63 (t, 1H, J=7.8 Hz), 8.30 (d, 1H, J=7.8 Hz), 8.35 (d, 1H, J=7.8Hz), 8.78 (s, 1H).

[0486] A solution of 2-nitroaniline (0.62 g, 4.5 mmol) andisoterephthalic acid monomethyl ester chloride (1.06 g, 5.3 mmol) in THF(5.6 mL) and pyridine (1.1 mL) was stirred for 2 h at room temperature.To this mixture was added saturated NaHCO₃(20 mL) and the mixtureextracted with ethyl acetate (3×20 mL). The combined organic extractswere dried (MgSO₄), filtered, concentrated and purified by columnchromatography on silica gel (5% MeOH/CH₂Cl₂) to afford(2-nitrophenyl)-isoterephthalamic acid methyl ester (0.70 g, 52%) as ayellow solid. ¹H NMR (CDCl₃) δ3.99 (s, 3H), 7.27 (t, 1H, J=7.8 Hz), 7.65(t, 1H, J=7.8 Hz), 7.75 (t, 1H, J=7.8 Hz), 8.17 (d, 1H, J=7.8 Hz), 8.30(t, 2H, J=7.8 Hz), 8.67 (s, 1H), 8.99 (d, 2H, J=7.8 Hz).

[0487] To a solution of (2-nitrophenyl)-isoterephthalamic acid methylester (0.70 g, 2.3 mmol) in glacial acetic acid (8 mL) was added ironpowder (<5 μm mesh, 0.35 g, 6.3 mmol) and the mixture stirred at refluxfor 1.5 h. The mixture was cooled, stirred at room temperature for 1 hand concentrated under reduced pressure. The residue was partitionedbetween saturated sodium bicarbonate (20 mL) and ethyl acetate (20 mL),the phases separated and the organic layer washed with saturated NaHCO₃(20 mL). The organic extract was dried (MgSO₄), filtered andconcentrated to give the cyclized methyl 3-(benzimidazol-2-yl)-benzoateester (0.59 g, 100%). ¹H NMR (CDCl₃) δ3.93 (s, 3H), 7.30 (m, 2H), 7.57(t, 2H, J=7.8 Hz), 7.88 (br, 1H), 8.12 (d, 1H, J=7.8 Hz), 8.35 (d, 1H,J=7.8 Hz), 8.64 (s, 1H), 10.10 (br, 1H (NH)).

[0488] To a solution of 3-(benzimidazol-2-yl)-benzoate ester (0.20 g,0.8 mmol) in THF (8 mL) at −78° C. was added a solution of DIBAL-H (4.0mL, 1.0 M in THF, 4.0 mmol). The reaction-was allowed to warm to roomtemperature, stirred for 0.5 h and quenched with a saturated potassiumsodium tartrate solution (15 mL). The biphasic mixture was stirredvigorously for 1 h, the phases separated and the organic layer dried(MgSO₄), filtered and concentrated to give 3-(benzimidazol-2-yl)-benzylalcohol (0.12 g, 67%). ¹H NMR (CD₄OD₃) δ4.73 (s, 2H), 7.26 (m, 2H), 7.52(m, 2H), 7.57 (m, 2H), 7.99 (m, 1H), 8.10 (s, 1H).

[0489] Using General Procedure C: To a solution of3-(benzimidazol-2-yl)-benzyl alcohol (0.12 g, 0.5 mmol) andtriethylamine (0.11 mL, 0.8 mmol) in THF (5 mL) was addedmethanesulfonyl chloride (55 μL, 0.7 mmol) and the mixture stirred atroom temperature for 1 h. The resultant mesylate (0.15 g, 91%) was usedwithout further purification in the next reaction. ¹H NMR (CDCl₃) δ3.14(s, 3H), 5.38 (s, 2H), 7.27 (m, 2H), 7.62 (m, 4H), 8.12 (m, 1H), 8.19(s, 1H).

[0490] Using the general alkylation procedure: A solution of themesylate from above (0.15 g, 0.5 mmol), N,N-diisopropylethylamine (0.12mL, 0.7 mmol) and potassium iodide (6 mg, 30 μmol) in CH₃CN (5 mL) wasreacted(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.18 g, 0.5 mmol) at 60° C. for 3 h. Purification of the crude bycolumn chromatography on silica gel (2% MeOH/CH₂Cl₂) gave the desiredN-alkylated product (0.17 g, 60%) as a flaky white solid. ¹H NMR (CDCl₃)δ1.68 (s, 10H), 2.05 (m, 2H), 2.30 (m, 1H), 2.80 (m, 2H), 3.69 (d, 1H,J=12.0 Hz), 3.87 (d, 1H, J=15.0 Hz), 4.30 (d, 1H, J=15.0 Hz), 4.45 (m,1H), 4.61 (d, 1H, J=15.0 Hz), 7.08 (m, 1H), 7.15-7.30 (m, 7H), 7.35 (d,1H, J=7.8 Hz), 7.67 (d, 2H, J=7.8 Hz), 7.70 (m, 3H), 8.09 (d, 1H, J=7.8Hz), 8.49 (d, 1H, J=3.5 Hz), 9.06 (s, 1H).

[0491] Using General Procedure D: Conversion of the material from above(50 mg) to the hydrobromide salt gave AMD9575 (0.062 g) as a beigesolid. ¹H NMR (D₂O) δ1.91 (br m, 1H), 2.25 (m, 2H), 2.45 (br m, 1H),3.04 (br m, 2H), 3.79 (d, 1H, J=12.9 Hz), 3.94 (d, 1H, J=13.2 Hz), 4.42(d, 1H, J=16.2 Hz), 4.62 (d, 1H, J=16.2 Hz), 4.78 (m, 1H), 7.14 (d, 2H,J=5.4 Hz), 7.14 (m, 2H), 7.41 (m, 2H), 7.48 (d, 2H, J=6.9 Hz), 7.59 (dd,2H, J=3.0, 6.3 Hz), 7.73 (dd, 2H, J=3.0, 6.0 Hz), 7.95 (t, 1H, J=6.9Hz), 8.41 (d, 1H, J=8.1 Hz), 8.79 (d, 1H, J=5.7 Hz); ¹³C NMR (D20)δ20.43, 21.15, 27.88, 50.15, 56.67, 63.59, 113.41 (2C), 114.16 (2C),122.13, 126.26, 126.54 (2C), 126.69, 127.03 (2C), 127.46, 130.33,130.83, 131.71, 135.08, 138.72, 139.91 (2C), 141.14, 147.47, 148.41(2C), 150.54, 151.56. ES-MS m/z 485 (M+H). Anal. Calcd. forC₃₁H₂₈N₆.3.0HBr.2.9H₂O: C, 48.35; H, 5.09; N, 10.37; Br, 29.60. Found:C, 48.35; H, 4.96; N, 10.31; Br, 29.59.

EXAMPLE: 73

[0492]

AMD9902: Preparation of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(imidazol-2-yl)-methylamine(hydrobromide salt)

[0493] Using standard reductive amination conditions A,1H-(benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(207 mg, 0.75 mmol) was stirred with imidazole-2-carboxaldehyde (96 mg,1.0 mmol) and sodium cyanoborohydride (95 mg, 1.5 mmol) in methanol (5mL) for 48 hours. The solution was then concentrated. The residue wastaken up in dichloromethane and washed with 1N sodium hydroxide (3 mL),then dried over anhydrous sodium sulfate, concentrated and purified bychromatography on silica gel (20:1 dichloromethane:methanol) to afford(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(imidazol-2-yl)-methylamine(69 mg, 56%). ¹H NMR (CDCl₃) δ1.64 (m, 1H), 1.86 (m, 1H), 2.00 (mn, 1H),2.68 (m, 1H), 2.86 (m, 1H), 3.64 (d, 1H, J=14.6 Hz), 3.79 (d, 1H, J=15.4Hz), 3.90 (m, 1H), 3.91 (d, 1H, J=15.4 Hz), 3.94 (d, 1H, J=14.6 Hz),6.97 (s, 1H), 7.18 (m, 3H), 7.55 (d, 1H, J=9.0 Hz), 7.60 (m, 2H), 8.47(d, 1H, J=4.9 Hz).

[0494](1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-(imidazol-2-yl)methylamine(56 mg, 0.156 mmol) was taken up in acetic acid (1 mL), to which asaturated solution of HBr in acetic acid (1 mL) was added. The mixturewas then stirred, precipitated and isolated as per procedure D to yieldAMD9902 as a white crystalline solid (39 mg). ¹H NMR (D₂O). δ1.88 (m,1H), 2.09 (m, 1H), 2.39 (m, 1H), 3.02 (m, 2H), 4.31 (d, 1H, J=15.6 Hz),4.42 (d, 1H, J=12.6 Hz), 4.48 (d, 1H, J=12.6 Hz), 4.53 (d, 1H, J=15.6Hz), 4.63 (m, 1H), 7.19 (s, 1H), 7.58 (m, 2H), 7.73 (m, 2H), 7.87 (dd,1H, J=7.8, 4.9 Hz), 8.67 (d, 1H, J=4.9 Hz). ¹³C NMR (D₂O) δ19.83, 20.26,20.94, 27.30, 27.71, 47.37, 48.09, 61.93, 114.33, 120.20, 126.27,126.64, 127.36, 131.08, 140.35, 140.98, 142.76, 148.42, 149.03, 151.26,154.87. ES-MS m/z 359 (M+H); Anal. Calcd. for (C₂₁H₂₂N₆×2.7 HBr×1.9H₂O×0.3 HOAc): C, 40.86; H, 4.87; N, 12.88; Br 36.73. Found: C, 41.11;H, 4.73; N, 12.87; Br, 36.39.

EXAMPLE: 74

[0495]

AMD9592: Preparation of4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-2,6-dichloropyridine(hydrobromidesalt)

[0496] Preparation of methanesulfonic acid2,6-dichloro-pyridin-4-ylmethyl ester

[0497] To a stirred solution of 2,6-dichloroisonicotinic acid (280 mg,1.5 mmol) in THF (7.5 mL) was added dropwise a solution of BH₃-THF (1Min THF, 5.8 mL, 5.8 mmol) and the mixture stirred at reflux 65 h. Thereaction was cooled, quenched with MeOH (10 mL) and concentrated underreduced pressure. To the resultant residue was added MeOH (10 mL) andthe solution re-concentrated. This procedure was repeated five times andthe resultant white solid (230 mg, 89%) was used without furtherpurification in the next step.

[0498] Using General Procedure C: To an stirred, ice-cooled solution ofthe material from above (230 mg, 1.3 mmol) and triethylamine (0.50 mL,3.9 mmol) in CH₂Cl₂ (13 mL) was added methanesulfonylchloride (0.10 mL,0.3 mmol) and the mixture stirred for 30 minutes at 0° C. The desiredcrude mesylate (340 mg) was obtained as a pale yellow solid and usedwithout further purification in the next step.

[0499] Using General Procedure for N-Alkylation: A solution of thematerial from above (330 mg, 1.3 mmol) and N,N-diisopropylethylamine(0.45 mL, 2.6 mmol) in CH₃CN (13 mL) was reacted with(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(470 mg, 1.2 mmol) overnight. Purification of the crude material byflash chromatography on silica gel (3:1 EtOAc/hexanes) provided thedesired amine (400 mg, 58%) as a pale yellow solid.

[0500] Using General Procedure D: Conversion of the material from above(264 mg, 0.49 mmol) to the hydrobromide salt with simultaneous removalof the N-tert-butoxycarbonyl protecting group gave AMD9592 (280 mg, 92%)as a white powder. ¹H NMR (D₂O) δ1.80-1.97 (m, 1H), 2.12-2.21 (m, 2H),2.33-2.45 (m, 1H), 2.97-3.01 (m, 2H), 3.83 (q, 2H, J=15 Hz), 3.78 (dd,2H, J=66, 15 Hz), 4.73 (m, 1H), 7.18(s, 2H), 7.47-7.51 (m, 2H),7.59-7.62 (m, 2H), 7.86 (t, 1H, J=6 Hz), 8.32 (d, 1H, J=7.5 Hz), 8.72(d, 1H, J=6 Hz), ¹³C NMR (CDCl₃) δ25.12, 25.90, 32.66, 54.46, 60.32,67.92, 118.95(2), 128.83(2), 131.11, 132.05(2), 135.43, 144.95, 146.02,153.17, 154.63, 154.87, 155.07, 157.53. ES-MS m/z 439 (M+H). Anal.Calcd. for C₂₃H₂₁N₅Cl₂.1.0H₂O.2.0HBr: C, 44.69; H, 4.08; N, 11.33 Br,25.85; Cl, 11.47. Found: C, 44.56; H, 4.22; N, 11.41; Br, 25.83; Cl,11.46.

EXAMPLE: 75

[0501]

AMD9782: Preparation of(1H-benzoimidazol-2-ylmethyl)-benzooxazol-5-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0502] Preparation of 5-bromomethyl-benzoxazole

[0503] A mixture of 5-methylbenzoxazole (200 mg, 1.50 mmol),N-bromosuccinimide (321 mg, 1.80 mmol), and 2,2′-azobisisobutyronitrile(37 mg, 0.23 mmol) in CCl₄ (3 mL) was heated at reflux for 22 h. Themixture was filtered and the filtrate was concentrated under reducedpressure. Purification of the crude material on silica gel (5%EtOAc/hexanes) gave the title compound as a colourless crystals (126 mg,39%). ¹H NMR (CDCl₃) δ4.64 (s, 2H), 7.46 (dd, 1H, J=8.6, 1.7 Hz), 7.57(d, 1H, J=8.4 Hz), 7.83 (d, 1H, J=1.2 Hz), 8.12 (s, 1H).

[0504] Using General Procedure for N-Alkylation: A solution of5-bromomethyl-benzoxazole (94 mg, 0.44 mmol), potassium iodide (3 mg,0.02 mmol), and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in CH₃CN(4 mL) was reacted with(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(152 mg, 0.402 mmol) at 60° C. for 22 h. Purification of the crudematerial by flash chromatography on silica gel (400:5:1EtOAc/MeOH/NH₄OH) gave a yellow foam (124 mg, 60%).

[0505] A solution of the yellow foam (40 mg, 0.078 mmol) in 3:1trifluoroacetic acid/CH₂Cl₂ (4 mL) was stirred at room temperature for 1hour then concentrated. The residue was partitioned between CH₂Cl₂ andsaturated NaHCO₃(aq), and the aqueous phase was extracted with CH₂Cl₂.The combined organic phases were dried (MgSO₄), filtered andconcentrated to give the title compound as a yellow foam (32 mg, 89%).¹H NMR (CDCl₃) δ1.68 (m, 1H), 2.04 (m, 2H), 2.28 (m, 1H), 2.71 (m, 1H),2.86 (m, 1H), 3.86 (s, 2H), 3.98 (d, 1H, J=17 Hz), 4.09 (m, 1H), 4.22(d, 1H, J=17 Hz), 7.19 (m, 3H), 7.44 (m, 3H), 7.58 (m, 2H), 7.87 (s,1H), 8.02 (s, 1H), 8.73 (d, 1H, J=4.2 Hz); ¹³C NMR (CDCl₃) δ21.77,23.76, 29.58, 48.77, 54.24, 60.59, 110.95, 120.86, 122.08, 122.75,126.73, 135.19, 136.57, 137.77, 140.56, 147.38, 149.70, 153.13, 156.32,157.63. ES-MS m/z 410 (M+H). Anal Calcd for (C₂₅H₂₃N₅O) 0.23(H₂O)0.53(CH₂Cl₂): C, 66.86; H, 5.39; N, 15.27. Found: C, 66.99; H, 5.55; N,14.90.

EXAMPLE: 76

[0506]

AMD9786: Preparation ofpyridin-2-ylmethyl-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine

[0507] Using General Procedure for N-Alkylation: 2-Bromomethyl pyridinehydrochloride (104 mg, 0.413 mmol) was stirred withN,N-diisopropylethylamine (0.092 mL, 0.516 mmol) in CH₃CN (5 mL) for 10min. Potassium carbonate (71 mg, 0.516 mmol) and(1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(130 mg, 0.344 mmol) were then added and the mixture was heated to 60°C. for 2 h. The dark solution was cooled, concentrated and the resultantthe residue was taken up in CH₂Cl₂ and washed with aqueous ammoniumcarbonate. Purification of the residue by chromatography on silica gel(10% MeOH/CH₂Cl₂) yielded the productpyridin-2-ylmethyl-(1H-N-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(32 mg, 20%) as a white foam. ¹H NMR (CDCl₃) δ1.62 (s, 9H), 1.88-2.20(m, 4H), 2.69-2.78 (m, 2H), 3.95 (d, 1H, J=16.1 Hz), 4.13 (d, 1H, J=16.1Hz), 4.36 (t, 1H, J=6.8 Hz), 4.63 (d, 1H, J=12.8 Hz), 4.77 (d, 1H,J=12.8 Hz), 6.86 (m, 1H), 6.96 (m, 1H), 7.22-7.29 (m, 3H), 7.38 (t, 1H,J=7.8 Hz), 7.62 (m, 2H), 7.74 (m, 1H), 8.30 (d, 1H, J=6.0 Hz), 8.43 (d,1H, J=5.2 Hz).

[0508] Using General Procedure D: Conversion of the foam from above (32mg, 0.068 mmol) to the hydrobromide salt gave AMD9786 (28 mg) as a whitesolid. ¹H NMR (D₂O). δ1.81 (m, 1H), 2.19 (m, 2H), 2.45 (m, 1H), 3.00 (m,2H), 4.23 (d, 1H, J=9.0 Hz), 4.38 (s, 1H), 4.43 (s, 1H), 4.59 (d, 1H,J=9.0 Hz), 4.77 (m, 1H), 7.46 (dd, 1H, J=5.3, 6.8 Hz), 7.53 (m, 2H),7.63 (m, 2H), 7.72 (d, 1H, J=8.1 Hz), 7.86 (dd, 1H, J=7.8, 5.7 Hz), 8.04(dt, 1H, J=7.8, 1.5 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.49 (d, 1H, J=5.1 Hz),8.70 (d, 1H, J=6.0 Hz). ¹³C NMR (D₂O) δ20.32, 21.06, 27.74, 48.17,55.59, 62.28, 114.23 (2C), 126.86, 126.16, 126.87, 127.16 (2C), 131.05,140.23, 140.95, 144.03, 144.78, 148.10, 149.33, 149.68, 152.40. ES-MSm/z 440 (M+H); Anal. Calcd. for (C₂₃H₂₃N₅×2.9 HBr×1.7 H₂O): C, 43.52; H,4.65; N, 11.03; Br 36.51. Found: C, 43.50; H, 4.68; N, 10.96; Br, 36.58.

EXAMPLE: 77

[0509]

AMD9787: Preparation of(1H-benzimidazol-2-ylmethyl)-benzoxazol-6-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0510] Preparation of 6-bromomethyl-benzoxazole

[0511] A mixture of 6-methylbenzoxazole (422 mg, 3.17 mmol),N-bromosuccinimide (677 mg, 3.80 mmol), and 2,2′-azobisisobutyronitrile(78 mg, 0.48 mmol) in CCl₄ (6.3 mL) was heated at reflux for 22 h. Themixture was filtered and the filtrate was concentrated under reducedpressure. Purification of the crude material on silica gel (4%EtOAc/hexanes) gave the title compound as colourless crystals (257 mg,38%). ¹H NMR (CDCl₃) δ4.64 (s, 2H), 7.42 (dd, 1H, J=8.1, 1.5 Hz), 7.64(d, 1H, J=1.2 Hz), 7.76 (d, 1H, J=8.4 Hz), 8.12 (s, 1H).

[0512] Using General Procedure for N-Alkylation: A solution of6-bromomethyl-benzoxazole (113 mg, 0.533 mmol), potassium iodide (4 mg,0.02 mmol), and N,N-diisopropylethylamine (0.12 mL, 0.69 mmol) in CH₃CN(4.4 mL) was reacted with(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(168 mg, 0.444 mmol) at 60° C. for 16 h. Purification of the crudematerial by flash chromatography on silica gel. Purification of thecrude material on silica gel (600:5:1 EtOAc/MeOH/NH₄OH) gave a yellowoil (179 mg, 79%).

[0513] A solution of the yellow oil (173 mg, 0.339 mmol) in 3:1trifluoroacetic acid/CH₂Cl₂ (4 mL) was stirred at room temperature for 1h then concentrated. The residue was partitioned between CH₂Cl₂ andsaturated NaHCO₃(aq), and the aqueous phase was extracted with CH₂Cl₂.The combined organic phases were dried (MgSO₄), filtered andconcentrated to give the title compound AMD9787 as a yellow foam (118mg, 79%). ¹H NMR (CDCl₃) δ1.70 (m, 1H), 2.04 (m, 2H), 2.29 (m, 1H), 2.73(m, 1H), 2.87 (m, 1H), 3.88 (s, 2H), 3.98 (d, 1H, J=17 Hz), 4.11 (m,1H), 4.22 (d, 1H, J=17 Hz), 7.19 (m, 3H), 7.42 (m, 2H), 7.62 (m, 3H),7.71 (s, 1H), 8.01 (s, 1H), 8.73 (d, 1H, J=4.2 Hz); ¹³C NMR (CDCl₃)δ21.23, 23.36, 29.06, 48.47, 53.88, 60.16, 110.74, 119.94, 121.52,122.26, 125.07, 134.68, 137.25, 137.65, 139.20, 146.86, 150.08, 152.34,155.73, 157.13. ES-MS m/z 410 (M+H). Anal Calcd for (C₂₅H₂₃N₅O) 0.6(H₂O)0.2(EtOAc): C, 70.76; H, 5.94; N, 15.99. Found: C, 70.88; H, 5.83; N,16.07.

EXAMPLE: 78

[0514]

AMD9829: Preparation of(1H-benzimidazol-4-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0515]

[0516] Preparation of 4-methyl-1H-benzimidazole

[0517] To a stirred solution of 2,3-diaminotoluene (1.00 g, 8.2 mmol) inCH₂Cl₂ (82 mL) was added trimethylorthoformate (4.5 mL, 41 mmol) andtrifluoroacetic acid (0.32 mL, 4.1 mmol) and the mixture stirred at roomtemperature for 24 h after which the reaction mixture was diluted withCH₂Cl₂ (200 mL), and washed consecutively with saturated aqueous NaHCO₃(40 mL) and H₂O (40 mL). The aqueous layers were reextracted with CH₂Cl₂(2×100 mL). The combined organic extracts were dried over MgSO₄ andconcentrated to a rusty brown solid (1.07 g, 97%)., ¹H NMR (300 MHz,CDCl₃) 6 8.08 (s, 1H), 7.49 (d, 1H, J=8.1 Hz), 7.23-7.18 (m, 1H), 7.10(d, 1H, J=7.5 Hz), 2.64 (s, 3H).

[0518] Preparation of 4-bromomethyl-benzimidazole-1-carboxylic acidtert-butyl ester

[0519] To a stirred solution of 4-methyl-1H-benzimidazole (1.05 g, 7.9mmol) in THF (10 mL) was added di-tert-butyl dicarbonate (4.4 g, 20mmol) in THF (6 mL). After 18 h the reaction mixture was concentrated toa brown syrup. Purification by column chromatography on silica gel(20:3—Hexanes:EtOAc) gave the desired product as a yellow syrup (1.66 g,91%). ¹H NMR (300 MHz, CDCl₃) δ8.41 (s, 1H), 7.81 (d, 1H, J=8.1 Hz),7.31-7.26 (m, 1H), 7.16 (d, 1H, J=7.5 Hz), 2.67 (s, 3H), 1.70 (s, 9H).

[0520] To a stirred solution of 4-methyl-benzimidazole-1-carboxylic acidtert-butyl ester (800 mg, 3.4 mmol) in CCl₄ (7 mL) was addedN-bromosuccinimide (730 mg, 4.1 mmol) and2,2′-azobis(2-methylpropionitrile) (84 mg, 0.51 mmol). The resultantmixture was heated at reflux for 18 h after which it was filtered andconcentrated to a yellow/orange syrup and crystals (1.4 g). Purificationby column chromatography on silica gel (200:15—Hexanes:EtOAc) gave thedesired title compound as a yellow syrup (635 mg, 60%). ¹H NMR (300 MHz,CDCl₃) δ8.48 (s, 1H), 7.95 (dd, 1H, J=7.8, 1.5 Hz), 7.42-7.34 (m, 2H),4.96 (s, 2H), 1.71 (s, 9H).

[0521] Using General Procedure for Alkylation: To a stirred solution of(1-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(153 mg, 0.40 mmol) and 4-bromomethyl-benzimidazole-1-carboxylic acidtert-butyl ester (167 mg, 0.48 mmol) in CH₃CN (5 mL) was added KI (3 mg,0.02 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) and thereaction mixture heated to 60° C. for 3 d. The resultant foam wasdissolved in a mixture of CH₂Cl₂ (2 mL) and TFA (2 mL). After 3 h thesolution was concentrated, redissolved in H₂O (˜1 mL) and basified with1N NaOH. The aqueous phase was extracted with CH₂Cl₂ (3×50 mL). Thecombined organic extracts were dried over MgSO₄ and concentrated to alight brown foam. Purification by column chromatography on silica gel(200:3:2—CH₂Cl₂:MeOH:NH₄OH) followed by radial chromatography on silicagel (1 mm plate, 100:1:1—CH₂Cl₂:MeOH:NH₄OH) afforded the desired productas a light yellow foam (38 mg, 23%). ¹H NMR (300 MHz, CDCl₃) δ8.59 (d,1H, J=3.6 Hz), 8.00 (s, 1H), 7.72 (d, 1H, J=7.0 Hz), 7.58-7.35 (m, 3H),7.20-713 (m, 5H), 4.19-4.08 (m, 3H), 3.97 (d, 1H, J=15 Hz), 3.84 (d, 1H,J=13.5 Hz), 2.90-2.75 (m, 2H), 2.54-2.50 (m, 1H), 2.15-2.11 (m, 1H),2.04-1.92 (m, 1H), 1.79-65 (m, 1H).

[0522] Following General Procedure D: Conversion of the foam from above(38 mg) to the hydrobromide salt gave AMD9829. ¹H NMR (300 MHz, D₂O)δ9.15 (s, 1H), 8.78 (dd, 1H, J=5.7, 1.2 Hz), 8.39 (d, 1H, J=8.1 Hz),7.92 (dd, 1H, J=7.8, 6.0 Hz), 7.49-7.42 (m, 3H), 7.41-7.36 (m, 2H), 7.28(t, 1H, J=8.1 Hz), 7.15 (d, 1H, J=8.1 Hz), 4.89-4.83 (m, 1H), 4.54 (d,1H, J=16.5 Hz), 4.40 (d, 1H, J=13.5 Hz), 4.34 (d, 1H, J=16.2 Hz), 4.16(d, 1H, J=13.5 Hz), 3.06-3.03 (m, 2H), 2.56-2.52 (m, 1H), 2.31-2.22 (m,2H), 1.97-1.94 (m, 1H); ¹³C NMR (75.5 MHz, D₂O) δ150.4, 148.2, 141.0,140.1, 140.0, 130.5, 130.0, 128.4, 126.9, 126.1, 123.7, 114.1, 113.6,66.5, 63.1, 52.8, 49.1, 27.9, 21.0, 20.5. ES-MS m/z 409.3 (M+H). AnalCalcd for (C₂₅H₂₄N₆).2.9(HBr).2.2(H2O): C, 43.98; H, 4.62; N, 12.31; Br,33.94. Found: C, 44.22; H, 4.75; N, 12.11; Br, 33.75.

EXAMPLE: 79

[0523]

AMD9780: Preparation of(1H-Benzimidazol-2-ylmethyl)-pyridin-4-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0524] Following General Procedure B: To a solution of(1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(120 mg, 0.32 mmol) and 4-pyridinecarboxaldehyde (30 μL, 0.32 mmol) inCH₂Cl₂ (5 mL) was added sodium triacetoxyborohydride (136 mg, 0.64 mmol)and the reaction stirred for 18 h. The resulting crude material wastaken up in neat TFA (1 mL) and stirred 3 h. Saturated aqueous sodiumbicarbonate (5 mL) was added, and the resulting mixture was extractedwith CH₂Cl₂ (3×10 mL) then the combined organic extracts were dried(MgSO₄), and concentrated in vacuo. Purification of the crude materialby radial chromatography (1 mm plate, 50:1:1 CH₂Cl₂-MeOH-NH₄OH) affordedthe title compound (83 mg, 70%) as a white solid. ¹H NMR (CDCl₃)δ1.68-1.72 (m, 1H), 1.97-2.06 (m, 2H), 2.26-2.30 (m, 1H), 2.74-2.77 (m,1H), 2.80-2.86 (m, 1H), 3.77 (s, 2H), 3.92 (d, 1H, J=16 Hz), 4.09 (dd,1H, J=9, 7 Hz), 4.17 (d, 1H, J=16 Hz), 7.18-7.22 (m, 3H), 7.36 (d, 2H,J=6 Hz), 7.44 (dd, 1H, J=7.1 Hz), 7.52 (br d, 1H, J=7 Hz), 7.66 (br d,1H, J=7 Hz), 8.46 (dd, 2H, J=5, 2 Hz), 8.70 (dd, 1H, J=5, 1 Hz); ¹³C NMR(CDCl₃) δ21.2, 23.8, 29.0, 49.1, 53.0, 60.5, 110.9, 118.8, 121.4, 121.9,122.5, 123.3, 133.7, 134.7, 137.4, 144.2, 146.9, 148.7, 149.8, 155.4,156.9. ES-MS m/z 370 (M+H). Anal. Calcd. for C₂₃H₂₃N₅.0.2H₂O.0.2CH₂Cl₂:C, 71.44; H, 6.15; N, 17.95. Found: C, 71.63; H, 6.30; N, 17.77.

EXAMPLE: 80

[0525]

AMD9781: Preparation of(1H-Benzimidazol-2-ylmethyl)-(benzo[1,3]dioxol-4-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0526] Following General Procedure B: To a solution of2,3-(methylenedioxy)-benzaldehyde (57 mg, 0.379 mmol) and[1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(140 mg, 0.371 mmol) in CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (107 mg,0.505 mmol) and the reaction stirred overnight. Purification of theresultant oil by radial chromatography on silica gel (2 mm TLC, 100:1:1CH₂Cl₂: CH₃OH: NH₄OH) gave the N-alkylated amine (105 mg). A solution ofthis amine in TFA (2 mL) was stirred for 1 h then concentrated underreduced pressure and the resultant crude material partitioned betweenCH₂Cl₂ (15 mL) and saturated aqueous NaHCO₃ (15 mL). The phases wereseparated and the organic layer was dried (Na₂SO₄), filtered,concentrated and purified by radial chromatography (1 mm TLC plate,125:1:1 CH₂Cl₂: CH₃OH: NH₄OH) to afford AMD9781 (45% over two steps). ¹HNMR (CDCl₃) δ1.61-1.76 (m, 1H), 1.93-2.09 (m, 2H), 2.21-2.31 (m, 1H),2.64-2.90 (m, 2H), 3.67 (d, 1H, J=14.0 Hz), 3.92 (d, 1H, J=13.8 Hz),4.03 (d, 1H, J=16.5 Hz), 4.11 (dd, 1H, J=9.2, 6.8 Hz), 4.21 (d, 1H,J=16.7 Hz), 5.89 (s, 2H), 6.64 (d, 1H, J=7.0 Hz), 6.71 (t, 1H, J=7.7Hz), 6.98 (d, 1H, J=8.1 Hz), 7.11-7.23 (m, 3H), 7.40 (d, 1H, J=7.6 Hz),7.55-7.63 (m, 2H), 8.64 (d, 1H, J=3.6 Hz). ¹³C NMR (CDCl₃) δ21.54,24.21, 29.31, 29.84, 47.82, 49.15, 60.63, 100.74, 107.42 (2 carbons),120.85, 121.70, 121.74 (2 carbons), 122.34 (2 carbons), 122.76 (2carbons), 134.80, 137.34 (2 carbons), 145.98, 146.95 (2 carbons),147.07, 156.34, 157.45. ES-MS m/z 413 (M+H) Anal Calc. forC₂₅H₂₄N₄O₂.0.8H₂O: C, 70.34; H, 6.04; N, 13.12. Found: C, 70.44; H,5.98; N, 12.88.

EXAMPLE: 81

[0527]

AMD9789: Preparation of benzo[1,3]dioxol-5-ylmethyl-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0528] Using General Procedure B: To a solution of[1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(125 mg, 0.33 mmol), piperonal (50 mg, 0.33 mmol) and AcOH (0.02 mL,0.33 mmol) in THF (3.3 mL) was added NaBH(OAc)₃ (210 mg, 0.99 mmol) andthe resultant suspension stirred at room temperature for 16 h. The crudeproduct was dissolved in a mixture of CH₂Cl₂ (˜2 mL) and trifluoroaceticacid (˜2 mL). After 1.5 h, the reaction mixture was concentrated,redissolved in H₂O (˜2 mL), and basified with 1N NaOH. The aqueoussolution was extracted with CH₂C₁₂ (3×50 mL) and the combined organicextracts were dried over MgSO₄ and concentrated to a yellow syrup. Theproduct was purified by column chromatography on silica gel(100:1:1—EtOAc:MeOH:NH₄OH) to give the titled compound as a white foam(45 mg, 33%). ¹H NMR (300 MHz, CDCl₃) δ8.69 (d, 1H, J=3.3 Hz), 7.58 (brs, 2H), 7.43 (d, 1H, J=7.2Hz), 7.21-7.16 (m, 3H), 6.99 (d, 1H, J=1.5Hz), 6.79 (dd, 1H, J=8.1, 1.5 Hz), 6.65 (d, 1H, J=7.8 Hz), 5.86-5.85 (m,2H), 4.15 (d, 1H, J=16.5 Hz), 4.09-4.06 (m, 1H), 3.98 (d, 1H, J=16.8Hz), 3.64 (s, 2H), 2.91-2.80 (m, 1H), 2.74-2.67 (m, 1H), 2.27-2.17 (m,1H), 2.06-1.64 (m, 2H), 1.75-1.64 (m, 1H), (m, 1H); ¹³C NMR (75.5 MHz,CDCl₃) δ159.2, 158.0, 149.4, 148.7, 148.5, 139.0, 136.5, 135.0, 124.0,123.5, 123.3, 110.7, 109.5, 102.5, 61.8, 55.5, 49.9, 31.0, 25.0, 23.1.ES-MS m/z 413.3 (M+H). Anal Calcd for (C₂₅H₂₄N₄O₂).0.8(H₂O): C, 70.34;H, 6.04; N, 13.12. Found: C, 70.29; H, 5.99; N, 12.75.

EXAMPLE: 82

[0529]

AMD9817: Preparation of(1H-Benzimidazol-2-ylmethyl)-(2,3-dihydro-benzofuran-7-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0530] Following General Procedure B: To a solution of2,3-dihydrobenzofuran-7-carboxaldehyde (53.6 mg, 0.362 mmol) and[1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(136 mg, 0.361 mmol) CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (112 mg, 0.528mmol) and the mixture stirred overnight. Purification of the crudeproduct by radial chromatography on silica gel (1 mm TLC plate, 125:1:1CH₂Cl₂: CH₃OH: NH₄OH) to gave the desired freebase (48 mg, 33%).

[0531] Following General Procedure D: Conversion of the amine from above(28 mg, 38%) gave AMD9817. ¹H NMR (D₂O) δ1.84-2.01 (m, 1H), 2.08-2.29(m, 2H), 2.34-2.54 (m, 2H), 2.70-2.83 (m, 1H), 2.95-3.12 (m, 2H), 3.39(d, 1H, J=12.7 Hz), 3.57 (d, 1H, J=12.6 Hz), 4.37 (d, 1H, J=16.2 Hz),4.48-4.73 (m, 3H) [4.60 (d, 1H, J=15.5 Hz)], 6.52-6.56 (m, 2H), 6.91(dd, 1H, J=6.1, 2.7 Hz), 7.50 (dd, 2H, J=6.3, 2.8 Hz), 7.58 (dd, 2H,J≦6.6, 3.0 Hz), 7.93 (dd, 1H, J=7.9, 5.9 Hz), 8.39 (d, 1H, J=7.0 Hz),8.73 (d, 1H, J=5.0 Hz). ¹³C NMR (D₂O) δ20.48, 20.86, 27.43, 28.73,50.35, 51.50, 63.64, 72.17, 113.74 (2 carbons), 117.76, 121.22, 125.49,126.17, 126.64, 127.73 (2 carbons), 129.77, 130.53, 138.83 (2 carbons),140.34, 147.85, 150.58, 151.78, 157.51. ES-MS m/z 411 (M+H) Anal Calc.for C₂₆H₂₆N₄O.2.2HBr.2.1H₂O: C, 49.86; H, 5.21; N, 8.94; Br, 28.07.Found: C, 50.16; H, 5.02; N, 9.03; Br, 27.68.

EXAMPLE: 83

[0532]

AMD9818: Preparation of(1H-Benzimidazol-2-ylmethyl)-pyridin-3-ylmethyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0533] Following General Procedure B: To a solution of3-pyridine-carboxaldehyde (29 mg, 0.271 mmol) and[1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(103 mg, 0.273 mmol) in CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (98 mg, 0.462mmol) and the reaction stirred overnight. Purification of the crudeproduct by radial chromatography (1 mm TLC plate, 80:1:1 CH₂Cl₂: CH₃OH:NH₄-OH) gave the desired freebase (64 mg, 50%).

[0534] Following General Procedure D: Conversion of the amine from above(64 mg) to the hydrobromide salt gave AMD9818 (69 mg, 78%). ¹H NMR (D₂O)6 1.80-1.96 (m, 1H), 2.16-2.31 (m, 2H), 2.43-2.54 (m, 1H), 3.01-3.08(mn, 2H), 4.10 (d, 1H, J=14.1 Hz), 4.24 (d, 1H, J=13.9 Hz), 4.43 (d, 1H,J=16.4 Hz), 4.61 (d, 1H, J=15.6 Hz), 4.72-4.75 (m, 1H), 7.58 (dd, 2H,J=6.5, 3.3 Hz), 7.69 (dd, 2H, J=6.4, 3.4 Hz), 7.81 (dd, 1H, J=8.2, 6.0Hz), 7.91 (dd, 1H, J=8.1, 6.0 Hz), 8.36-8.41 (m, 2H), 8.54 (d, 1H, J=8.0Hz), 8.74-8.79 (mn, 2H). ¹³C NMR (D₂O) δ14.54, 20.29, 20.76, 27.83,48.39, 53.46, 61.54, 66.47, 114.23 (2 carbons), 126.30, 127.29 (2carbons), 127.42, 130.76, 137.43, 140.23, 141.21, 141.25, 141.63,147.43, 148.44, 149.92, 150.13. ES-MS m/z 370 (M+H) Anal Calc. forC₂₃H₂₃N₅.3.0HBr.1.8H₂O: C, 42.85; H, 4.63; N, 10.86; Br, 37.19. Found:C, 43.22; H, 4.66; N, 10.69; Br, 36.85.

EXAMPLE: 84

[0535]

AMD9828: Preparation of(1H-benzoimidazol-5-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt).

[0536]

[0537] Preparation of 1H-benzoimidazole-5-carbaldehyde

[0538] LiAlH₄ (1.0 m in THF, 10 mL, 10 mmol) was added dropwise to asuspension of 5-benzimidazolecarboxylic acid (500 mg, 3.08 mmol) in THF(20 mL) at 0° C. The reaction mixture was warmed to room temperature andstirred for 24 h followed by heating at 50° C. for an addition 24 h.MeOH (4×5 mL) was added and the solution was concentrated between eachaddition. The resulting brown syrup was dried in vacuo for 3 h. Thesyrup was dissolved in 100:1—CH₂Cl₂:MeOH, filtered through celite andconcentrated to a light brown foam (300 mg, 66%). To a stirred solutionof the crude alcohol (300mg, 2.0 mmol) in CH₂Cl₂ (10 mL) and MeOH (0.8mL) was added manganese (IV) oxide (85%, 2.05 g, 20 mmol). Thesuspension was heated to 40° C. for 18 h, cooled to room temperature andfiltered through celite. The filtrant was concentrated to a light yellowfoam (260 mg). Purification of the crude material by columnchromatography on silica gel (200:1:1—EtOAc:MeOH: NH₄OH) gave the titlecompound as a white powder (139 mg, 60%). ¹H NMR (300 MHz, CD₃OD) δ10.0(s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 7.87 (d, 1H, J=9.0 Hz), 7.75 (d,1H, J=9.0 Hz)

[0539] Using General Procedure BA: To a solution of[1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(215 mg, 0.57 mmol), 1H-benzoimidazole-5-carbaldehyde (81 mg, 0.57 mmol)and AcOH (0.03 mL, 0.55 mmol) in TKF (5.5 mL) was added NaBH(OAc)₃ (353mg, 1.65 mmol) and the suspension stirred at room temperature for 24 h.The crude product was dissolved in a mixture of CH₂Cl₂ (˜2 mL) andtrifluoroacetic acid (18 2 mL). After 3 h, the reaction mixture wasconcentrated, redissolved in H₂O (˜2 mL), and basified with 1N NaOH. Theaqueous solution was extracted with CH₂Cl₂ (3×50 mL) and the combinedorganic extracts were dried over MgSO₄ and concentrated to a yellowfoam. The product was purified by column chromatography on silica gel(100:2:1—EtOAc:MeOH:NH₄OH) to give the titled compound as a light yellowfoam (52 mg, 24%). ¹H NMR (300 MHz, CDCl₃) δ8.68 (d, 1H, J=3.3 Hz), 7.95(s, 1H), 7.56 (br s, 4H), 7.41 (d, 1H, J=6.6 Hz), 7.27 (d, 1H, J=7.5Hz), 7.18-7.14 (m, 3H), 4.15 (d, 1H, J=16.8 Hz), 4.10-4.06 (m, 1H), 4.00(d, 1H, J=16.8 Hz), 3.85 (d, 1H, J=13.2 Hz), 3.77 (d, 1H, J=13.5 Hz),2.90-2.73 (m, 1H), 2.73-2.68 (m, 1H), 2.26-2.21 (m, 1H), 2.08-2.00 (m,2H), 1.79-1.64 (m, 1H).

[0540] Following General Procedure D: Conversion of the foam from above(52 mg) to the hydrobromide salt gave AMD9828. ¹H NMR (300 MHz, D₂O)δ8.81-8.78 (m, 2H), 8.43 (d, 1H, J=6.9 Hz), 7.95 (dd, 1H, J=8.1, 6 Hz),7.54-7.51 (m, 2H), 7.44-7.35 (m, 5H), 4.85-4.79 (m, 1H), 4.64 (d, 1H,J=16.2 Hz), 4.46 (d, 1H, J=16.2 Hz), 4.07 (d, 1H, J=12.9 Hz), 4.00 (d,1H, J=12.9 Hz), 3.08-3.05 (m, 2H), 2.51-2.48 (m, 1H), 2.35-2.22 (m, 2H),1.98-1.93 (m, 1H); ¹³C NMR (75.5 MHz, D₂O) δ151.7, 150.6, 148.4, 141.1,139.9, 136.8, 135.8, 130.1, 129.8, 129.5, 128.9, 126.8, 126.2, 115.2,114.7, 113.4, 63.5, 57.3, 50.0, 27.9, 21.1, 20.5. ES-MS m/z 409.3 (M+H).Anal Calcd for (C₂₅H₂₄N₆).2.9(HBr).3.0(H₂O): C, 43.07; H, 4.76; N,12.05; Br, 33.24. Found: C, 43.12; H, 4.65; N, 11.71; Br, 33.39.

EXAMPLE: 85

[0541]

AMD9844: Preparation ofBis-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0542] Following General Procedure for N-Alkylation: To a stirredsolution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(7.64 g, 28.5 mmol) in dry CH₃CN (3 mL) was added1-N-tert-butoxycarbonyl-2-chloromethylbenzimidazole (115 mg, 0.41 mmol),N,N-diisopropylethylamine (0.13 mL, 0.74 mmol), and potassium iodide (3mg, 0.02 mmol) and the mixture was stirred under an argon atmosphere at60° C. for 4 h. The crude yellow oil was dissolved in dry CH₂Cl₂ (2 mL)and trifluoroacetic acid (1 mL) was added dropwise. The resultantmixture was stirred overnight at room temperature. The reaction mixturewas diluted with CH₂Cl₂ (10 mL) and then concentrated in vacuo to removeany excess trifluoroacetic acid. The concentrate was diluted with CH₂Cl₂(20 mL) and extracted with 1N NaOH (30 mL). The aqueous layer was washedwith CH₂Cl₂ (2×15 mL) and then the combined organic layers were dried(Na₂SO₄), filtered, and concentrated in vacuo. Purification by radialchromatography on a 2mm TLC grade silica gel plate (CH₂Cl₂/MeOH/NH₄OH,100:1:1 followed by 50:1:1) afforded the dibenzimidazole adduct (134 mg,49%, 2 steps) as a colourless oil.

[0543] Using General Procedure D: Conversion of the free base (134 mg,0.33 mmol) to the hydrobromide salt gave AMD9844 as a beige solid (192mg). ¹H NMR (D20) δ1.87-2.04 (br m, 1H), 2.15-2.37 (m, 2H), 2.41-2.55(br m, 1H), 2.99-3.12 (m, 2H), 4.46 (d, 2H, J=15.6 Hz), 4.65 (d, 2H,J=15.6 Hz), 4.92 (dd, 1H, J=10.2, 6.3 Hz), 7.34-7.44(m, 8H), 7.90 (dd,1H, J=8.1, 6.0 Hz), 8.38 (d, 1H, J=7.8 Hz), 8.76 (d, 1H, J=5.7 Hz); ¹³CNMR (D₂O) δ20.29, 21.27, 27.77, 48.75, 63.05, 113.81, 126.33, 127.28,130.82, 140.52, 141.10, 148.45, 148.80, 148.92; ES-MS m/z 409 (M+H).Anal. Calcd. for C₂₅H₂₄N₆.3.0HBr.1.8H₂O.0.3C₄H₁₀O: C, 44.58; H, 4.80; N,11.91; Br, 33.96. Found: C, 44.52; H, 4.68; N, 11.91; Br, 33.94.

EXAMPLE: 86

[0544]

AMD9875: Preparation of(1H-Benzimidazol-2-ylmethyl)-(3H-imidazol-4-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0545] Using General Procedure B: Reaction of4(5)-imidazolecarboxaldehyde (0.055 g, 0.57 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.164 g, 0.43 mmol) with NaBH(OAc)₃ (0.154 g, 0.73 mmol) in CH₂Cl₂ (4mL) for 24 hours followed by purification of the crude material byradial chromatography on silica gel (2 mm plate, 20:1:1CH₂Cl₂-CH₃OH-NH₄OH) provided 0.099 g (50%) of the desired tertiary amineas a white solid.

[0546] Using General Procedure D: Conversion of the white solid (99 mg)to the hydrobromide salt with simultaneous removal of the BOC-protectinggroup, followed by re-precipitation of the intermediate solid frommethanol/ether, gave AMD9875 (97 mg) as a white solid. ¹H NMR (D₂O)δ1.83-1.97 (m, 1H), 2.15-2.26 (m, 2H), 2.39-2.46 (m, 1H), 3.03-3.05 (m,2H), 4.05 (d, 1H, J=15.0 Hz), 4.21 (d, 1H, J=15.0 Hz), 4.44 (d, 1H,J=16.2 Hz), 4.59 (d, 1H, J=16.2 Hz), 4.75 (dd, 1H, J=6.0, 10.2 Hz), 7.35(s, 1H), 7.59-7.65 (m, 2H), 7.73-7.78 (m, 2H), 7.90 (dd, 1H, J=6.6, 7.2Hz), 8.38 (d, 1H, J=8.1 Hz), 8.48 (s, 1H), 8.72 (d, 1H, J=5.7 Hz); ¹³CNMR (D₂O) δ20.32, 20.66, 27.72, 46.28, 48.05, 61.54, 114.16, 118.98,126.13, 127.27, 129.11, 130.73, 134.90, 140.07, 140.87, 148.31, 149.87,150.31; ES-MS m/z 359 (M+H). Anal. Calcd. for C₂₁H₂₂N₆.3.0 HBr.2.6 H₂O:C, 38.92; H, 4.70; N, 12.97; Br, 36.99. Found: C, 39.02; H, 4.59; N,12.72; Br, 37.02.

EXAMPLE: 87

[0547]

AMD9575: Preparation of[4-(1H-benzimidazol-2-yl)-benzyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(hydrobromide salt)

[0548] Preparation of 4-(benzimidazol-2-yl)-benzaldehyde

[0549] A solution of 2-nitroaniline (0.41 g, 3.0 mmol) and methyl4-chlorocarbonyl benzoate (0.65 g, 3.3 mmol) in THF (3.7 mL) andpyridine (0.8 mL) was stirred for 2 h at room temperature. The reactionwas diluted with saturated sodium bicarbonate (10 mL) and EtOAc (15 mL),the phases separated and the aqueous phase extracted with EtOAc (2×10mL). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford(2-nitrophenyl)-terephthalamic acid methyl ester as a yellow solid (0.70g, 78%). ¹H NMR (CDCl₃) δ3.97 (s, 3H), 7.25 (t, 1H, J=7.8 Hz), 7.74 (t,1H, J=7.8 Hz), 8.04 (d, 2H, J=7.8 Hz), 8.20 (s, 1H (NH)), 8.20 (d, 2H,J=7.8 Hz), 8.3 (d, 1H, J=7.8 Hz), 8.99 (d, 1H, J=7.8 Hz).

[0550] To a solution of (2-nitrophenyl)-terephthalamic acid methyl ester(0.23 g, 0.76 mmol) in glacial acetic acid (2.5 mL) was added ironpowder (<5 μm mesh, 0.12 g, 2.1 mmol) and the mixture stirred at refluxfor 1 h. The mixture was cooled, stirred at room temperature for 2 h andconcentrated under reduced pressure. The residue was partitioned betweensaturated sodium bicarbonate (10 mL) and ethyl acetate (10 mL), thephases separated and the organic layer washed with saturated NaHCO₃ (10mL). The organic extract was dried (MgSO₄), filtered and concentrated togive cyclized methyl 4-(benzimidazol-2-yl)-benzoate (0.163 g, 86%). ¹HNMR (CDCl₃) δ3.96 (s, 3H), 7.32 (m, 2H), 7.53 (br, 1H), 7.84 (br, 1H),8.17 (m, 4H), 9.65 (br, 1H (NR)).

[0551] To a solution of methyl 4-(benzimidazol-2-yl)-benzoate (0.23 g,0.9 mmol) in THF (10 mL) at 0° C. was added a solution of DIBAL-H (5.0mL, 1.0 M in THF, 5.0 mmol). The reaction was allowed to warm to roomtemperature, stirred for 1 h and quenched with a saturated potassiumsodium tartrate solution (20 mL). The biphasic mixture was stirredvigorously for 1 h, the phases separated and the organic layer dried(MgSO4), filtered, concentrated and purified by column chromatography onsilica gel (7% MeOH/CH₂Cl₂) to give 4-(benzimidazol-2-yl)-benzyl alcohol(0.175 g, 87%). ¹H NMR (CD₄OD) δ3.30 (s, 1H (OH)), 4.69 (s, 2H), 7.26(m, 2H), 7.53 (d, 2H, J=8.4 Hz), 7.60 (m, 2H), 8.07 (d, 2H, J=8.1 Hz).

[0552] 4-(Benzimidazol-2-yl)-benzyl alcohol from above (0.175 g, 0.78mmol) was dissolved in CH₂Cl₂ (5 mL) and THF (8 mL), treated withactivated MnO₂ (0.68 g, 7.8 mmol) and stirred at room temperature for1.5 h. The mixture was filtered through celite, the cake washed withCH₂Cl₂ and the solvent from the eluent removed under reduced pressure toafford 4-(benzimidazol-2-yl)-benzaldehyde (92 mg, 42%). ¹H NMR CD₄OD)δ7.28 (m, 2H), 7.60 (br, 1H (NH)), 7.65 (d, 2H, J=7.8 Hz), 8.09 (d, 2H,J=7.8 Hz), 8.30 (d, 2H, J=9.0 Hz), 10.08 (s, 1H (CHO)).

[0553] Using General Procedure B: To a solution4-(benzimidazol-2-yl)-benzaldehyde (39 mg, 0.175 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(60 mg, 0.16 mmol) in THF (2 mL) was added acetic acid (90 μL) andsodium triacetoxyborohydride (68 mg, 0.32 mmol) and the mixture stirredat 60° C. for 3 h. Purification of the crude product by radialchromatography on silica gel (0.7%MeOH/0.5%NH₄OH/CH₂Cl₂) afforded thedesired[4-(1H-benzimidazol-2-yl)-benzyl]-(N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(30 mg, 39%) as a flaky white solid. ¹H NMR (CDCl₃) δ1.72 (s, 10H), 1.97(m, 2H), 2.26 (m, 1H), 2.73 (m, 2H), 3.80 (d, 1H, J=15.0 Hz), 4.00 (d,1H, J=15.0 Hz), 4.35 (m, 1H), 4.71 (s, 2H), 7.00 (m, 1H), 7.14 (m, 2H),7.24 (m, 3H), 7.33 (d, 2H, J=7.2 Hz), 7.47 (br, 1H), 7.53 (d, 1H, J=7.2Hz), 7.63 (d, 1H, J=7.8 Hz), 7.67 (d, 2H, J=7.8 Hz), 7.79 (br, 1H), 8.39(d, 1H, J=3.5 Hz), 9.92 (br, 1H (NH)).

[0554] Using General Procedure D: Conversion of the material from above(30 mg) to the hydrobromide salt to provide AMD9575 (0.026 g) as a whitesolid. ¹H NMR (D₂O) δ1.92 (br m, 1H), 2.25 (m, 2H), 2.47 (br m, 1H),3.06 (br m, 2H), 3.78 (d, 1H, J=12.9 Hz), 3.92 (d, 1H, J=12.6 Hz), 4.44(d, 1H, J=16.5 Hz), 4.63 (d, 1H, J=15.9 Hz), 4.80 (m, 1H), 7.01 (dd, 2H,J=6.0, 3.2 Hz), 7.37 (d, 2H, J=8.1 Hz), 7.43 (dd, 2H, J=3.2, 6.0 Hz),7.54 (d, 2H, J=8.1 Hz), 7.58 (dd, 2H, J=3.0, 6.3 Hz), 7.74 (dd, 2H,J=3.0, 6.3 Hz), 7.97 (t, 1H, J=6.9 Hz), 8.44 (d, 1H, J=7.8 Hz), 8.81 (d,1H, J=5.4 Hz); ¹³C NMR (D₂O) δ19.74, 20.48, 27.23, 49.56, 55.99, 62.95,113.15 (2C), 113.40 (2C), 120.78 (2C), 125.49 (2C), 125.62, 126.33 (2C),126.41 (2C), 129.83, 130.79 (2C), 139.23 (2C), 140.50, 141.69, 146.89,147.76 (2C), 149.95, 150.89. ES-MS m/z 485 (M+H). Anal. Calcd. forC₃₁H₂₈N₆.3.0HBr.3.6H₂O: C, 46.90; H, 4.86; N, 10.59; Br, 30.35. Found:C, 46.93; H 4.74; N, 10.41; Br, 30.34.

EXAMPLE: 88

[0555]

AMD9719: Preparation of(1H-Benzimidazol-2-ylmethyl)-(4-pyrid-2-yl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0556] Following General Procedure B: To a solution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(174 mg, 0.462 mmol) and 4-pyrid-2-yl-benzenecarboxaldehyde (161 mg,0.879 mmol) in CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (192 mg, 0.906 mmol)and the mixture stirred overnight. Purification of the crude material byradial chromatography (2mm TLC plate, 100:1:1 CH₂Cl₂/CH₃OH/NH₄OH)provided the free base (0.135 g, 66%).

[0557] Following General Procedure D: Conversion of the material fromabove (135 mg) to the hydrobromide salt gave AMD9719 (0.154 g, 69%). ¹HNMR (D₂O) δ1.86-2.00 (m, 1H), 2.19-2.37 (m, 2H), 2.44-2.54 (m, 1H),3.03-3.11 (m, 2H), 3.90 (d, 1H, J=12.7 Hz), 3.98 (d, 1H, J=13.2 Hz),4.50 (d, 1H, J=16.4 Hz), 4.68 (d, 1H, J=16.6 Hz), 7.29 (dd, 2H, J=6.4,3.3 Hz), 7.40-7.48 (m, 4H), 7.53 (dd, 2H, J=6.2, 3.1 Hz), 7.69 (d, 1H,J=8.5 Hz), 7.90-7.99 (m, 2H), 8.44 (d, 1H, J=7.9 Hz), 8.51 (t, 1H, J=8.0Hz), 8.62 (d, 1H, J=5.6 Hz), 8.81 (d, 1H, J=5.3 Hz). ¹³C NMR (D₂O)δ19.95, 20.58, 27.38, 49.79, 56.32, 63.04, 113.36 (2 carbons), 125.41,125.71, 125.78, 126.21 (2 carbons), 127.29 (2 carbons), 129.66, 129.93,130.91 (2 carbons), 139.31, 140.63, 140.95, 146.80 (2 carbons), 147.89(2 carbons), 150.18, 150.59, 151.15. ES-MS m/z 446 (M+H) Anal Calc. forC₂₉H₂₇N₅.3.1HBr.2.0H₂O: C, 47.56; H, 4.69; N, 9.56; Br, 33.82. Found: C,47.60; H, 4.76; N, 9.44; Br, 33.93.

EXAMPLE: 89

[0558]

AMD9750: Preparation of(1H-Benzimidazol-2-ylmethyl)-[4-(oxazol-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(hydrobromide salt)

[0559] Preparation of 4-(oxazol-2-yl)-benzyl alcohol (B. A. Anderson etal. J. Org. Chem. 1997, 62, 8634)

[0560] To a solution of oxazole (0.285 mL, 4 mmol) in THF (40mL) at −78°C. was added n-butyllithium (1.83 mL of a 2.4M solution in hexanes, 4.4mmol) and the reaction stirred for 30 min at −78° C. then zinc chloride(12 mL of 1M solution in THF, 12 mmol) was added. The mixture was thenallowed to slowly warm to 0° C. and was stirred for 45 min. A solutionof methyl-4-bromobenzoate (0.860 g, 4 mmol) in THF (10 mL) was addedfollowed by a solution of bis-(triphenylphosphine)-palladium (II)chloride (140 mg, 0.2 mmol) and n-butyllithium (0.17 mL of a 2.4Msolution in hexanes, 0.4 mmol) in THF (4 mL). The resultant dark brownmixture was warmed to reflux and stirred for 1 h. After cooling, thereaction mixture was diluted with ethyl acetate (30 mL), then washedwith water (1×20 mL) and brine (1×20 mL). The organic layer was dried(Na₂SO₄), filtered, concentrated and purified by chromatography onsilica gel (98:2 CH₂Cl₂/MeOH) to give the desiredmethyl-4-(oxazol-2-yl)-benzoate (340 mg, 42%) as a yellow oil. ¹H NMR(CDC1₃) δ3.94 (s, 3H), 7.28 (s, 1H), 7.76 (m, 1H), 8.09 (m, 4H).

[0561] To a solution of methyl-4-(oxazol-2-yl)-benzoate (0.203 g, 1mmol) in CH₂Cl₂ (10 mL) 0° C. was added DIBAL-H (4 mL of a 1.0M solutionin dichloromethane, 4 mmol) over 10 min. The resultant solution wasstirred at 0° C. for 2 h then quenched with an aqueous saturatedsolution of sodium potassium tartrate (20 mL) and the biphasic mixturestirred rapidly for 60 min. The phases were separated and the aqueouslayer extracted with CH₂Cl₂ (3×10 mL). The combined organic fractionswere dried (Na₂SO₄), filtered, concentrated and purified bychromatography on silica gel (10:1 CH₂Cl₂/MeOH) to afford the titlealcohol (0.156 g, 89%). ¹H NMR (CDCl₃) δ3.42 (t, 1H, J=6.0 Hz (OH)),4.77 (s, 2H, J=6.0 Hz), 7.24 (s, 1H), 7.47 (d, 2H, J=7.8 Hz), 7.71 (s,11H), 8.05 (d, 2H, J=7.8 Hz).

[0562] Using General Procedure C: To a solution of4-(oxazol-2-yl)-benzyl alcohol (156 mg, 0.89 mmol) in CH₂Cl₂ (10 mL) wasadded methanesulfonyl chloride (0.102 mL, 1.34 mmol) and triethylamine(0.250 mL, 1.79 mmol) and the mixture stirred for 30 min at roomtemperature. The resultant mesylate was obtained as a fine white powderand used directly in the next reaction without further purification. ¹HNMR (CDCl₃) δ3.00 (s, 3H), 3.67 (s, 2H), 7.26 (s, 1H), 7.51 (d, 2H,J=8.1 Hz), 7.74 (s, 1H), 8.07 (d, 2H, J=8.1 Hz).

[0563] Using the general alkylation procedure: To a solution of themesylate from above (56 mg, 0.22 mmol), K₂CO₃ (60 mg, 0.44 mmol) and KI(2 mg, 0.01 mmol) in CH₃CN (10 mL) was added(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(113 mg, 0.3 mmol) and the mixture stirred at 60° C. for 16 h.Purification of the crude material by chromatography on silica gel (10:1CH₂Cl₂/MeOH) afforded the N-alkylated product (89 mg, 93%). ¹H NMR(CDCl₃) δ1.73 (s, 9H), 2.03 (m, 3H), 2.20 (m, 1H), 2.75 (m, 2H), 3.81(d, 1H, J=16.1 Hz), 4.04 (d, 11H, J=16.1 Hz), 4.34 (dd, 1H, J=9.1, 6.2Hz), 4.67 (s, 2H), 7.03 (m, 1H), 7.11-7.17 (m, 2H), 7.26 (m, 4H),7.57-7.68 (m, 5H), 8.44 (d, 1H, J=5.1 Hz).

[0564] Using General Procedure D: Conversion of the amine from above (89mg, 0.020 mmol) to the hydrobromide salt gave AMD9750 (14 mg) as a whitesolid. ¹H NMR (D₂O). δ2.07 (m, 1H), 2.26 (m, 2H), 2.44 (m, 1H), 3.05 (m,2H), 3.81 (m, 3H), 4.42 (d, 1H, J=16.2 Hz), 4.63 (d, 1H, J=16.2 Hz),7.18 (s, 1H), 7.24 (m, 2H), 7.43 (m, 2H), 7.83 (s, 1H), 7.83 (t, 1H,J=7.8 Hz), 8.43 (d, 1H, J=8.4 Hz), 8.82 (d, 1H, J=5.2 Hz). ¹³C NMR (D₂O)δ20.42, 21.07, 27.83, 50.22, 56.69, 63.49, 113.67 (2C), 125.02, 126.14(2C), 126.23 (2C), 126.69, 140.41, 130.81 (2C), 139.74, 140.35, 141.01,148.33, 150.69, 151.41, 156.23, 161.09. ES-MS m/z 436 (M+H); Anal.Calcd. for (C₂₇H₂₅N₅O×2.9 HBr×2.0 H₂O): C, 45.92; H, 4.55; N, 9.92; Br32.81. Found: C, 46.01; H, 4.65; N, 9.55; Br, 32.75.

EXAMPLE: 90

[0565]

AMD9755: Preparation of(1H-Benzimidazol-2-ylmethyl)-(4-imidazol-1-yl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0566] Using General Procedure B: Reaction of4-(imidazol-1-yl)benzaldehyde (0.075 g, 0.44 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.107 g, 0.29 mmol) with NaBH(OAc)₃ (0.171 g, 0.81 mmol) in CH₂Cl₂ (3mL) for 24 h followed by purification of the crude material by columnchromatography on silica gel (25:1:1 CH₂Cl₂-CH₃OH-NH₄OH) provided 0.091g (58%) of the desired tertiary amine as a white solid.

[0567] Using General Procedure D: Conversion of the white solid (91 mg)to the hydrobromide salt with simultaneous removal of the BOC-protectinggroup, followed by re-precipitation of the intermediate solid frommethanol/ether, gave AMD9755 (89 mg) as a white solid. ¹H NMR (D₂O)δ1.86-2.02 (m, 1H), 2.22-2.36 (m, 2H), 2.48-2.52 (m, 1H) 3.06-3.08(m,2H), 3.90 (d, 1H, J=12.6 Hz), 3.98 (d, 1H, J=12.6 Hz), 4.90 (d, 1H,J=16.5 Hz), 4.69 (d, 1H, J=16.5 Hz), 4.79-4.87 (m, 1H, overlaps withHOD), 7.22 (d, 2H, J=8.7 Hz), 7.31 (dd, 1H, J=1.2, 1.5 Hz), 7.39-7.46(m, 4H), 7.54-7.61 (m, 3H), 7.98 (dd, 1H, J=6.0, 7.8 Hz), 8.45 (d, 1H,J=7.5 Hz), 8.67 (s, 1H), 8.82 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ21.03,21.67, 28.46, 50.80, 57.18, 64.09, 114.49, 121.28, 121.87, 122.61,126.80, 127.32, 131.06, 132.52, 134.10, 134.84, 139.32, 140.40, 141.74,148.99, 151.26, 152.38; ES-MS m/z 435 (M+H). Anal. Calcd. forC₂₇H₂₆N₆.3.2 HBr.3.4 H₂O: C, 42.97; H, 4.81; N, 11.14; Br, 33.88. Found:C, 43.00; H, 4.61; N, 10.89; Br, 33.93.

EXAMPLE: 91

[0568]

AMD9757: Preparation of[4-(thiazol-2-yl)-benzyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(hydrobromide salt)

[0569] Preparation of 4-(2-thiazolyl)-benzaldehyde

[0570] To a solution of 2-bromothiazole (0.26 g, 1.6 mmol) and4-formylphenylboronic acid (0.48 g, 3.2 mmol) in toluene (16mL) wasadded tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.08 mmol) andK₂CO₃ (0.33 g, 2.4 mmol) and the solution stirred at reflux for 16 h.The reaction was cooled to room temperature, diluted with water (50 mL)and ethyl acetate (50 mL). The organic layer was separated, washed withbrine (30 mL), dried (MgSO₄), filtered, concentrated and purified bycolumn chromatography on silica gel (2% MeOH/CH₂Cl₂) to give4-(2-thiazolyl)-benzaldehyde (45 mg, 15%). ¹H NMR (CDCl₃) δ7.45 (d, 1H,J=3.0 Hz), 7.90 (d, 1H, J=3.0 Hz), 7.97 (d, 2H, J=7.8 Hz), 8.15 (d, 2H,J=7.2 Hz), 10.07 (s, 1H (CHO)).

[0571] Using General Procedure B: To a solution of4-(2-thiazolyl)-benzaldehyde (45 mg, 0.24 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(81 mg, 0.21 mmol) in dichloromethane (2.5 mL) was added NaBH(OAc)₃ (77mg, 0.36 mmol) and the mixture stirred at room temperature for 16 h.Purification of the crude by radial chromatography on silica gel(MeOH/NH₄OH/CH₂Cl₂, 1:1:98) gave the desired amine (34 mg, 28%) as aflaky white solid. ¹H NMR (CDCl₃) δ1.73 (m, 10H), 1.97 (m, 2H), 2.25 (m,1H), 2.75 (m, 2H), 3.84 (d, 1H, J=15.0 Hz), 4.03 (d, 1H, J=15.0 Hz),4.32 (m, 1H), 4.68 (s, 2H), 7.02 (m, 1H), 7.10 (t, 1H, J=7.2 Hz), 7.18(t, 1H, J=7.2 Hz), 7.27 (m, 4H), 7.58 (d, 2H, J=7.8 Hz), 7.60 (m, 2H),7.78 (d, 1H, J=3.0 Hz), 8.45 (d, 1H, J=3.5 Hz).

[0572] Using General Procedure D: Conversion of the solid from above (34mg) to the hydrobromide salt provided AMD9757 (34 mg) as a white solid.¹H NMR (D₂O) δ1.86 (br m, 1H), 2.23 (m, 2H), 2.43 (br m, 1H), 3.03 (brm, 2H), 3.70 (d, 1H, J=12.6 Hz), 3.84 (d, 1H, J=12.6 Hz), 4.42 (d, 1H,J=16.5 Hz), 4.62 (d, 1H, J=16.5 Hz), 4.77 (m, 1H), 7.21 (d, 2H, J=12.6Hz), 7.22 (d, 2H, J=8.7 Hz), 7.40 (d, 2H, J=8.1 Hz), 7.45 (dd, 2H,J=3.0, 6.0 Hz), 7.66 (d, 1H, J=3.3 Hz), 7.83 (d, 1H, J 3.6 Hz), 7.94 (t,1H, J=6.9 Hz), 8.40 (d, 1H, J=7.5 Hz), 8.78 (d, 1H, J=5.1 Hz); ¹³C NMR(D₂O) δ20.43, 21.07, 27.85, 50.29, 56.73,63.57, 113.70 (2C), 121.82,126.19, 126.58 (4C), 130.42, 131.10 (2C), 139.75 (2C), 140.01, 140.13(2C), 141.08, 148.36 (2C), 150.78, 151.54. ES-MS m/z 452 (M+H). Anal.Calcd. for C₂₇H₂₅N₅S.3.0HBr.2.0H₂O: C, 44.21; H, 4.41; N, 9.55; Br,33.04. Found: C, 44.26; H, 4.37; N, 9.29; Br, 33.04.

EXAMPLE: 92

[0573]

AMD9595: Preparation of(1H-Benzimidazol-2-ylmethyl)-[4-(benzothiazol-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(hydrobromide salt)

[0574]

[0575] Preparation of 4-(benzothiazol-2-yl)-benzyl alcohol

[0576] To a 0° C. solution of methyl-4-(benzothiazol-2-yl)-benzoate(prepared as described by A. Brembilla, D. Roizard and P. Lochon Synth.Commun. 1990, 20, 3379) (1.08g, 4 mmol) in THF (20 mL) was added DIBAL-H(20 mL of a 1.0 M solution in THF, 20 mmol) over 10 minutes. Theresulting solution was stirred at 0° C. for 2 hours, then an aqueoussaturated solution of sodium potassium tartrate was added and thebiphasic mixture stirred rapidly for 60 min. The phases were separatedand the aqueous layer extracted with ether (3×20 mL). The combinedorganic fractions were dried (Na₂SO4), concentrated and purified bycolumn chromatography on silica gel (10:1 CH₂Cl₂/MeOH) to afford thetitle compound (0.69g, 75%). ¹H NMR (CD₃OD) δ4.69 (s, 2H), 7.43 (t, 1H,J=7.8 Hz), 7.53 (m, 3H), 7.99 (m, 1H), 8.06 (m, 3H).

[0577] Using General Procedure C: To a solution of4-(benzothiazol-2-yl)-benzyl alcohol (227 mg, 1.0 mmol) in CH₂Cl₂ (10mL) was added methanesulfonyl chloride (0.092 mL, 1.2 mmol) andtriethylamine (0.210 mL, 1.5 mmol) and the mixture stirred at roomtemperature for 30 min. The mesylate was collected as a fine whitepowder and used without further purification in the next reaction. ¹HNMR (CDCl₃) δ3.06 (s, 3H), 5.28 (s, 2H), 7.38 (t, 1H, J=6.2 Hz), 7.49(t, 1H, J=6.2 Hz), 7.52 (d, 2H, J=7.1 Hz), 7.90 (d, 1H, J=6.2 Hz), 8.05(d, 1H, J-6.2 Hz), 8.11 (d, 2H, J=7.1 Hz).

[0578] Using the general alkylation procedure: A solution of themesylate from above (1 mmol), N,N-diisopropylethylamine (0.093 mL, 1.2mmol), potassium iodide (13 mg, 0.10 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(400 mg, 1.1 mmol) in CH₃CN (10 mL) was stirred at 70° C. for 3 h.Purification of the crude material by column chromatography on silicagel (10:1 CH₂Cl₂/MeOH) afforded the alkylated product(1H-N-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-[4-(benzothiazol-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(354 mg, 71%). ¹H NMR (CDCl₃) δ1.63 (s, 9H), 2.06 (m, 3H), 2.25 (m, 1H),2.75 (m, 2H), 3.81 (d, 1H, J=16.1 Hz), 4.02 (d, 1H, J=16.1 Hz), 4.34(dd, 1H, J=8.3, 6.8 Hz), 4.65 (d, 1H J=13.2 Hz), 4.69 (d, 1H, J=13.2Hz), 7.03 (m, 1H), 7.09-7.11 (m, 2H), 7.30 (m, 4H), 7.46 (t, 1H, J=8.1Hz), 7.62 (t, 2H, J=6.1 Hz), 7.69 (d, 1H, J=6.1 Hz), 7.85 (d, 1H, J=6.1Hz), 8.00 (d, 1H, J=6.1 Hz), 8.44 (d, 1H, J=4.8 Hz).

[0579] Using General Procedure D: Conversion of the material from above(80 mg) to the hydrobromide salt with simultaneous removal of theN-tert-butoxycarbonyl protecting group gave AMD9595 (14 mg) as a whitecrystalline solid. ¹H NMR (D₂O). δ1.85 (m, 1H), 2.18 (m, 2H), 2.41 (m,1H), 3.08 (m, 2H), 3.48 (m, 1H), 3.54 (dd, 1H, J=14.1, 7.2 Hz), 3.71 (d,1H, J=11.7 Hz), 4.40 (d, 1H, J=15.9 Hz), 4.60 (d, 1H, J=15.9 Hz), 7.00(dd, 1H, J=6.0, 3.0 Hz), 7.11 (d, 2H, J=7.8 Hz), 7.41 (m, 4H), 7.50 (d,J=7.8 Hz), 7.55 (t, 1H, J=7.2 Hz), 7.89 (d, 1H, J=8.1 Hz), 7.97 (m, 2H),8.43 (d, 1H, J=8.1 Hz), 8.79 (d, 1H, J=5.1 Hz). ¹³C NMR (D₂O) δ20.46,21.08, 26.83, 51.44, 56.69, 62.35, 113.56 (2C), 121.81, 122.57, 126.26,126.44, 126.94, 130.27, 130.61, 139.73, 140.02, 148.43, 151.69, 151.44,158.83. ES-MS m/z 501 (M+H); Anal. Calcd. for (C₃₁H₂₇N₅S×3 HBr×3 H₂O):C,46.63; H, 4.54; N, 8.77; Br 30.02. Found: C, 46.88; H, 4.46; N, 8.66;Br, 29.84.

EXAMPLE: 93

[0580]

AMD9615: Preparation of[4-(benzoxazol-2-yl)-benzyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(hydrobromide salt)

[0581] Preparation of 4-(benzoxazol-2-yl)-benzyl alcohol

[0582] A solution of 2-nitrophenol (0.50 g, 3.6 mmol) and methyl4-chlorocarbonyl benzoate (0.79 g, 4.0 mmol) in THF (4.5 mL) andpyridine (0.9 mL) was stirred for 1 h at room temperature. The reactionwas diluted with saturated sodium bicarbonate (10 mL) and EtOAc (15 mL),the phases separated and the aqueous phase extracted with EtOAc (2×10mL). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated under reduced pressure to afford(2-nitrophenyl)-terephthalic acid diester as a yellow solid (1.03 g,96%). ¹H NMR (CDCl₃) δ3.98 (s, 3H), 7.40 (d, 1H, J=7.8 Hz), 7.47 (t, 1H,J=7.8 Hz), 7.74 (t, 1H, J=7.2 Hz), 8.18 (d, 1H, J=7.2 Hz), 8.19 (d, 2H,J=7.8 Hz), 7.47 (t, 1H, J=2H, J=7.8 Hz).

[0583] To a solution of (2-nitrophenyl)-terephthalic acid diester (1.02g, 3.3 mmol) in glacial acetic acid (11 mL) was added iron powder (<5 μmmesh, 0.51 g, 9.0 mmol) and the mixture stirred at reflux for 1.5 h. Themixture was cooled, stirred at room temperature for 2 h and concentratedunder reduced pressure. The residue was partitioned between saturatedsodium bicarbonate (25 mL) and ethyl acetate (25 mL), the phasesseparated and the organic layer washed with saturated NaHCO₃ (25 mL).The organic extract was dried (MgSO4), filtered, concentrated andpurified by column chromatography on silica gel (2% MeOH/CH₂Cl₂) to give(2-hydroxyphenyl)-terephthalamic acid methyl ester (0.37 g, 44%). ¹H NMR(CDCl₃) δ3.98 (s, 3H), 6.95 (t, 1H, J=7.8 Hz), 7.07 (d, 1H, J=7.8 Hz),7.19 (t, 1H, J=7.8 Hz), 7.28 (d, 1H, J=7.8 Hz), 7.98 (d, 2H, J=8.4 Hz),8.18 (d, 2H, J=7.8 Hz).

[0584] A solution of (2-hydroxyphenyl)-terephthalamic acid methyl ester(0.35 g, 1.3 mmol) in polyphosphoric acid (5 mL) was heated to refluxfor 3 h. The solution was cooled to 0° C., water added (100 mL) andsolid K₂CO₃ introduced until pH 7-9 was attained. The residue wasdiluted with ethyl acetate (2×100 mL) and the organic extract dried(MgSO₄), filtered and concentrated to give cyclized methyl4-(benzoxazol-2-yl)-benzoate (0.15 g, 45%) as a beige powder. ¹H NMR(CDCl₃) δ3.98 (s, 3H), 7.40 (m, 2H), 7.61 (m, 1H), 7.81 (m, 1H), 8.20(d, 2H, J=7.8 Hz), 8.34 (d, 2H, J=7.8 Hz).

[0585] To a solution of methyl 4-(benzoxazol-2-yl)-benzoate (0.20 g, 0.8mmol) in THF (8 mL) at −78° C. was added a solution of DEBAL-H (4.0 mL,1.0 M in THF, 4.0 mmol). The reaction was allowed to warm to roomtemperature, stirred for 1 h and quenched with a saturated potassiumsodium tartrate solution (15 mL). The biphasic mixture was stirredvigorously for 1 h, the phases separated and the organic layer dried(MgSO₄), filtered and concentrated to give the title alcohol (0.16 g,89%). ¹H NMR (CDCl₃) δ1.80 (t, 1H (OH)), 4.82 (d, 2H, J=6.0 Hz), 7.36(m, 2H), 7.55 (d, 2H, J=8.4 Hz), 7.60 (m, 1H), 7.78 (m, 1H), 8.26 (d,2H, J=8.4 Hz).

[0586] Using General Procedure C: To a solution of4-(benzoxazol-2-yl)-benzyl alcohol (0.16 g, 0.7 mmol) and triethylamine(0.15 mL, 1.1 mmol) in THF (7 mL) was added methanesulfonyl chloride (75μL, 1.0 mmol) and the mixture stirred at room temperature for 0.5 h. Thereaction was quenched with a saturated solution of NaHCO₃ (10 mL) andthe aqueous phase was extracted with CH₂Cl₂ (3×10 mL). The combinedorganic extracts were dried (MgSO₄), filtered and concentrated to givethe mesylate (0.20 g, 93%) as a pale yellow crystalline solid. ¹H NMR(CDCl₃) δ3.00 (s, 3H), 5.33 (s, 2H), 7.38 (m, 2H), 7.60 (m, 3H), 7.78(m, 1H), 8.32 (d, 2H, J=7.8 Hz).

[0587] Using the general alkylation procedure: A solution of themesylate from above (0.20 g, 0.66 mmol), N,N-diisopropylethylamine (0.17mL, 1.0 mmol) and potassium iodide (6 mg, 30 μmol) in CH₃CN (7 mL) wasreacted(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.27 g, 0.72 mmol) at 60° C. for 4 h. Purification of the crude bycolumn chromatography on silica gel (4% MeOH/CH₂Cl₂), gave theN-alkylated product (0.23 g, 59%) as a flaky white solid. ¹H NMR (CDCl₃)δ1.74 (s, 10H), 2.01 (m, 2H), 2.26 (m, 1H), 2.74 (m, 2H), 3.87 (d, 1H,J=15 Hz), 4.08 (d, 1H, J=15 Hz), 4.35 (m, 1H), 4.70 (s, 2H), 7.00-7.20(m, 3H), 7.30-7.40 (m, 5H), 7.55-7.65 (m, 3H), 7.68 (m, 1H), 7.87 (d,2H, J=7.8 Hz), 8.42 (d, 1H, J=3.5 Hz).

[0588] Using General Procedure D: Conversion of the material from above(90 mg) to the hydrobromide salt gave AMD9615 (0.10 g) as a pale brownsolid. ¹H NMR (D₂O) δ1.86 (br m, 1H), 2.08 (m, 2H), 2.34 (br m, 1H),3.00 (br m, 2H), 3.04 (d, 1H), 3.50 (d, 1H, J=12.3 Hz), 4.30 (d, 1H,J=16.2 Hz), 4.52 (d, 1H, J=16.2 Hz), 4.66 (m, 1H), 6.91 (br d, 2H),J=7.2 Hz), 6.95 (d, 2H, J=8.1 Hz), 7.30 (br s, 2H), 7.32 (s, 2H), 7.35(d, 2H, J=8.7 Hz), 7.49 (br m, 2H), 7.98 (t, 1H, J=6.8 Hz), 8.44 (d, 1H,J=7.8 Hz), 8.76 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ20.32, 21.00, 27.87,50.20, 55.90, 63.25, 111.25, 113.57 (2C), 119.04, 124.64, 125.47, 126.12(2C), 126.26 (2C), 126.99 (2C), 130.29 (2C), 139.68 (2C), 13 140.26,141.00, 148.49 (2C), 149.88, 150.63, 151.29, 162.00. ES-MS m/z 486(M+H). Anal. Calcd. for C₃₁H₂₇N₅O2.1HBr.0.9H₂O: C, 55.18; H, 4.62; N,10.38; Br, 25.28. Found: C, 55.18; H, 4.65; N, 10.39; Br, 25.28.

EXAMPLE: 94

[0589]

AMD9716: Preparation of[4-(1H-imidazol-2-yl)-benzyl]-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine(hydrobromide salt)

[0590] Preparation of methyl [(N-sulfonic aciddimethylamide)-imidazol-2-yl]-benzyl alcohol

[0591] To a solution of imidazole-1-sulfonic acid dimethylamide (1.03 g,5.9 mmol) in THF (5.9 mL) at −78° C. was added n-butyllithium (3.2 mL,2.42 M in THF) and the solution stirred at −78° C. for 15 min. To thismixture was added a solution of zinc chloride (0.80 g, 5.9 mmol) in THF(4.4 mL) at −78° C. and the reaction warmed to room temperature andstirred for 0.5 h. To the resultant mixture was addedtetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.2 mmol), a solutionof methyl 4-bromobenzoate (0.85 g, 3.9 mmol) in THF (2.6 mL) and zincchloride (1.6 g, 11.8 mmol) and the reaction heated to reflux for 6 h.The reaction was quenched with saturated NH₄Cl (50 mL), the layersseparated and the organic layer washed with brine (1×30 mL), dried(MgSO₄), filtered, concentrated and purified by column chromatography onsilica gel (2% MeOH/CH₂Cl₂) to give methyl [(N-sulfonic aciddimethylamide)-imidazol-2-yl]-benzoate (0.56 g, 47%) as a brown solid.¹H NMR (CDCl₃) δ2.53 (s, 6H), 3.95 (s, 3H), 7.14 (s, 1H), 7.48 (s, 1H),7.79 (d, 1H, J=7.8 Hz), 8.12 (d, 1H, J=7.8 Hz).

[0592] To a solution of methyl [(N-sulfonic aciddimethylamide)-imidazol-2-yl]-benzoate (0.56 g, 1.8 mmol) in THF (18 mL)at −78° C. was added a solution of DIBAL-H (9.1 mL, 1.0 M in THF). Thereaction was allowed to warm to room temperature, stirred for 1 h andquenched with a saturated potassium sodium tartrate solution (25 mL).The biphasic mixture was stirred vigorously for 1 h, the phasesseparated and the organic layer dried (MgSO₄), filtered and concentratedto give methyl [(N-sulfonic acid dimethylamide)-imidazol-2-yl]-benzylalcohol (0.39 g, 76%). ¹H NMR (CDCl₃) δ2.49 (s, 6H), 4.72 (s, 2H), 7.10(s, 1H), 7.36 (d, 2H, J=7.2 Hz), 7.45 (s, 1H), 7.61 (d, 2H, J=7.2 Hz).

[0593] Using General Procedure C: To a solution of the alcohol fromabove (0.39 g, 1.4 mmol) and triethylamine (0.30 mL, 2.1 mmol) in THF(14 mL) was added methanesulfonyl chloride (0.15 mL, 1.9 mmol) and themixture stirred at room temperature for 1 h. The resultant mesylate(0.50 g) was used used without further purification in the nextreaction. ¹H NMR (CDCl₃) δ2.54 (s, 6H), 3.00 (s, 3H), 3.68 (s, 2H), 7.13(s, 1H), 7.46 (s, 1H), 7.48 (d, 2H, J=7.8 Hz), 7.75 (d, 2H, J=7.8 Hz).

[0594] Using the general alkylation procedure: A solution of themesylate from above (0.29 g, 0.8 mmol), N,N-diisopropylethylamine (0.21mL, 1.2 mmol) and potassium iodide (10 mg, 40 μmol) in CH₃CN (9 mL) wasreacted(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.31 g, 0.8 mmol) at 60° C. for 16 h. Purification of the crude bycolumn chromatography on silica gel (6% MeOH/CH₂Cl₂) gave the desiredamine (0.25 g, 48%) as a flaky white solid. ¹H NMR (CDCl₃) δ1.72 (s,10H), 1.93 (m, 2H), 2.13 (m, 1H), 2.27 (s, 6H), 2.74 (m, 2H), 3.90 (d,1H, J=15 Hz), 4.25 (d, 1H, J=15 Hz), 4.26 (m, 1H), 4.55 (d, 1H, J=15Hz), 4.65 (d, 1H, J=15 Hz), 7.00 (m, 2H), 7.26 (m, 4H), 7.44 (m, 4H),7.66 (m, 1H), 7.75 (m, 1H), 8.44 (d, 1H, J=3.5 Hz).

[0595] A solution of the protected imidazolyl-amine from above (0.25 g,0.5 mmol) in 2 M HCl (4 mL) was heated to reflux for 16 h. The mixturewas diluted with 15% aqueous NaOH (20 mL) and extracted with CH₂Cl₂(2×20 mL). The organic layer was separated, dried (MgSO₄), filtered,concentrated and purified by column chromatography on silica gel (5%MeOH/CH₂Cl₂) to give the desired amine (0.10 g, 60%) as a white solid.¹H NMR (CDCl₃) δ1.60 (m, 1H), 1.85 (m, 2H), 2.13 (m, 1H), 2.74 (m, 2H),3.52 (d, 1H, J=13.5 Hz), 3.62 (d, 1H, J=13.5 Hz), 3.88 (d, 1H, J=16.5Hz), 4.00 (m, 1H), 4.06 (d, 1H, J=16.5 Hz), 7.02 (s, 2H), 7.15-7.25 (m,5H), 7.38 (d, 1H, J=7.8 Hz), 7.57 (m, 2H), 7.66 (d, 2H, J=8.1 Hz), 8.63(d, 1H, J=4.2 Hz).

[0596] Using General Procedure D: Conversion of the solid from above(100 mg) to the hydrobromide salt gave AMD9716 (0.125 g) as a whitesolid. ¹H NMR (D₂O) δ1.87 (br m, 1H), 2.26 (m, 2H), 2.47 (br m, 1H),3.05 (br m, 2H), 3.87 (d, 1H, J=12.6 Hz), 3.94 (d, 1H, J=12.9 Hz), 4.45(d, 1H, J=16.2 Hz), 4.64 (d, 1H, J=16.2 Hz), 4.75 (m, 1H), 7.25 (dd, 2H,J=3.0, 6.0 Hz), 7.37 (s, 4H), 7.42 (s, 2H), 7.47 (dd, 2H, J=3.0, 6.0Hz), 7.95 (t, 1H, J=8.4 Hz), 8.42 (d, 1H, J=8.1 Hz), 8.80 (d, 1H, J=5.7Hz); ¹³C NMR (D₂O) δ28.72, 29.38, 36.15, 58.51, 65.13, 71.86, 122.09(2C), 128.20 (2C), 130.21, 134.22 (2C), 134.43 (3C), 138.98, 139.62(2C), 148.16 (2C), 149.34 (2C), 156.51 (2C), 159.04, 159.98. ES-MS m/z435 (M+H). Anal. Calcd. for C₂₇H₂₆N₆.3.2HBr.1.4H₂O: C, 45.61; H, 4.74;N, 11.34; Br, 34.64. Found: C, 45.61; H, 4.81; N, 11.37; Br, 34.65.

EXAMPLE: 95

[0597]

AMD 9841: Preparation of(2′-Aminomethyl-biphenyl-4-ylmethyl)-(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0598] Using the general alkylation procedure: To a solution of(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(0.194 g, 0.51 mmol) in CH₃CN (5 mL) was added N,N-diisopropylethylamine(0.30 mL, 1.72 mmol) followed by 4′-bromomethyl-2-cyanobiphenyl (0.303g, 1.11 mmol) and the resultant mixture heated to 60° C. for 25 h.Purification of the crude material by column chromatography on silicagel (10:1:1 CH₂Cl₂—CH₃OH—NH₄OH) followed by radial chromatography onsilica gel (2 mm plate, 100:1:1 CH₂Cl₂—CH₃OH—NH₄OH) provided a tan foam(79 mg).

[0599] The intermediate from above (79 mg, 0.14 mmol) was dissolved inNH₃ saturated methanol (3 mL) in a Parr hydrogenation bottle. Raneynickel (50 mg) was rinsed with MeOH (3×), transferred into thehydrogenation flask containing the nitrile and the mixture washydrogenated at 50 psi for 24 h. The mixture was filtered throughCelite® and the cake was washed with methanol. The eluant wasconcentrated under reduced pressure. Purification of the crude materialby radial chromatography on silica gel (1 mm plate, 50:1:1CH₂Cl₂—CH₃OH—NH₄OH) provided 36 mg (54%) of the free base of the titlecompound as a white foam.

[0600] Using General Procedure D: Conversion of the white foam (36 mg)to the hydrobromide salt, followed by re-precipitation of theintermediate solid from methanol/ether, gave AMD9841 (35 mg) as a whitesolid. ¹H NMR (D2O) δ1.87-2.00 (m, 1H), 2.22-2.39 (m, 2H), 2.45-2.51 (m,1H), 3.06-3.09 (m, 2H), 3.84-3.96 (m, 4H), 4.53 (d, 1H, J=16.5 Hz), 4.70(d, 1H, J=16.5 Hz), 4.78-4.85 (m, 1H, overlaps with HOD), 6.26 (d, 1H,J=7.2 Hz), 6.96 (d, 2H, J=7.8 Hz), 7.31 (d, 2H, J=7.8 Hz), 7.34-7.43 (m,3H), 7.51-7.55 (m, 2H), 7.60-7.64 (m, 2H), 7.96 (dd, 1H, J=6.0, 8.1 Hz),8.44 (d, 1H, J=7.8 Hz), 8.79 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ20.50,21.00, 27.90, 40.58, 50.45, 56.75, 63.43, 113.93, 126.12, 126.78,128.91, 128.99, 129.14, 129.36, 130.05, 130.55, 130.57, 131.06, 135.97,139.48, 139.71, 141.05, 141.20, 148.30, 150.94, 152.15; ES-MS m/z 474(M+H). Anal. Calcd. for C₃₁H₃₁N₅.3.0 HBr. 2.2 H₂O: C, 49.25; H, 5.12; N,9.26; Br, 31.71. Found: C, 49.31; H, 5.21;,N, 9.13; Br, 31.62.

EXAMPLE: 96

[0601]

AMD9785: Preparation of(1H-Benzimidazol-2-ylmethyl)-(2′-methoxy-biphenyl-4-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0602]

[0603] Preparation of 2′-methoxy-biphenyl-4-carboxaldehyde

[0604] To a stirred degassed solution of 4-bromobenzaldehyde (218 mg,1.18 mmol) and 2-methoxybenzeneboronic acid (188 mg, 1.24 mmol) inDME/THF (5 mL, 4:1) were added a 2 M Na₂CO₃ solution (1.6 mL) andPd(PPh₃)₄ (63 mg, 0.055 mmol). The reaction mixture was flushed withargon and maintained under argon while being heated at 85° C. overnight.The mixture was then cooled and diluted with EtOAc (25 mL) and water (25mL). The aqueous layer was washed with EtOAc (2×10 mL) and the combinedorganic extracts dried (Na₂SO₄), filtered and concentrated. Purificationof the resultant oil by column chromatography with silica gel(Hexanes/Et₂O, 80:20) afforded the title compound (230 mg, 92%) as aclear oil. ¹H NMR (CDCl₃) δ3.84 (s, 3H), 7.01-7.09 (m, 2H), 7.33-7.39(m, 2H), 7.71 (d, 2H, J=6 Hz), 7.93 (d, 2H, J=6 Hz), 10.05 (s, 1H).

[0605] Using General Procedure B: To a stirred solution of(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(95 mg, 0.25 mmol) and 2′-methoxy-biphenyl-4-carboxaldehyde (55 mg, 0.26mmol) in CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (83 mg, 0.39 mmol) and theresultant mixture was stirred at room temperature overnight.Purification of the crude material by radial chromatography on silicagel gel (1 mm plate, 50:1:1 CH₂Cl₂/MeOH/NH₄OH) afforded the desiredamine (75 mg, 52%) as a clear oil.

[0606] Using General Procedure D: Conversion of the oil from above (34mg, 0.059 mmol) to the hydrobromide salt with simultaneous removal ofthe N-tert-butoxycarbonyl protecting group followed by re-precipitationof the intermediate solid from methanol/ether gave AMD9785 (25 mg, 63%)as a white solid. ¹H NMR (D₂O) δ1.89-1.94 (m, 1H), 2.20-2.27 (m, 2H),2.31-2.44 (m, 1H), 3.03-3.05 (m, 2H), 3.68 (s, 3H), 3.76 (d, 1H, J=12.3), 3.84 (d, 1H, J=12.3 Hz), 4.47 (d, 1H, J=16.5 Hz), 4.63 (d, 1H, J=16.5Hz), 4.74-4.89 (m, 1H, overlap with HOD), 6.36 (d, 1H, J=7.5 Hz), 6.96(t, 1H, J=7.5 Hz), 7.02-7.05 (m, 3H), 7.19 (d, 2H, J=7.8 Hz), 7.33 (dd,1H, J=8.1, 7.8 Hz), 7.44 (dd, 2H, J=6, 3 Hz), 7.56 (dd, 2H, J=6, 3 Hz),7.93 (dd, 1H, J=7.2, 6.6 Hz), 8.40 (d, 1H, J=7.8 Hz), 8,76 (d, 1H, J=5.7Hz); ¹³C NMR (D₂O) δ19.71, 20.15, 27.08, 49.63, 55.13, 55.91, 62.54,111.67, 113.02, 120.58, 125.29, 125.91, 128.68, 129.09, 129.32, 129.76,130.34, 134.47, 137.26, 138.86, 140.17, 147.45, 150.22, 151.23, 155.17.ES-MS m/z 475 (M+H). Anal. Calcd. for C₃₁H₃₀N₄O.2.1HBr.1.3H₂O: C, 55.74;H, 5.24; N, 8.39; Br, 25.12. Found: C, 55.67 ; H, 5.26; N, 8.27; Br,25.30.

EXAMPLE: 97

[0607]

AMD9791: Preparation of(1H-Benzimidazol-2-ylmethyl)-(4-oxazol-5-yl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0608] Preparation of 4-(oxazol-5-yl)benzaldehyde

[0609] To a stirred solution of the 4-(oxazol-5-yl)benzyl alcohol(prepared as described by Tanaka, A.; Terasawa, T.; Hagihara, H.;Sakuma, Y.; Ishibe, N.; Sawada, M.; Takasugi, H.; Tanaka, H. J. Med.Chem. 1998, 41, 2390-2410) (0.23 g, 1.31 mmol) in CH₂Cl₂/MeOH (20:1,10.5 mL) was added activated MnO₂ (1.01 g, 11.6 mmol) and the mixturestirred at room temperature overnight. The reaction was then dilutedwith CH₂Cl₂ (10 mL) and filtered through Celite®, washing with CHCl₃.The filtrate was concentrated to give the crude aldehyde as a beigesolid (0.164 g) which used without further purification in the nextreaction. ¹H NMR (CDCl₃) δ7.52 (s, 1H), 7.82 (d, 2H, J=9 Hz), 7.95 (d,2H, J=9 Hz), 7.99 (s, 1H), 10.02 (s, 1H).

[0610] Using General Procedure B: To a stirred solution of(1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(133 mg, 0.35 mmol) and 4-(oxazol-5-yl)benzaldehyde (80 mg, 0.45 mmol)in CH₂Cl₂ (10 mL) was added NaBH(OAc)₃ (107 mg, 0.50 mmol) and theresultant mixture was stirred at room temperature overnight. Theresultant crude oil was dissolved in CH₂Cl₂/TFA (1:1, 2 mL) and themixture stirred for 2 h. The reaction was then concentrated and dilutedwith CH₂Cl₂ (30 mL) and 1 N NaOH (30 mL). The aqueous layer was washedwith CH₂Cl₂ (2×10 mL) and the combined organic extracts were dried(Na₂SO₄), filtered and concentrated. Purification of the crude foam byradial chromatography on silica gel gel (2 mm plate, 50:1:1CH₂Cl₂/MeOH/NH₄OH) afforded the free amine (50 mg, 33% over 2 steps) asa yellow foam.

[0611] Using General Procedure D: Conversion of the foam from above (50mg, 0.11 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD9791 (70 mg, 87%) asa yellow solid. ¹H NMR (D₂O) δ1.86-1.90 (m, 1H), 2.16-2.27 (m, 2H),2.38-2.43 (m, 1H), 2.99-3.02 (m, 2H), 3.60 (d, 1H, J=12.3 Hz), 3.76 (d,1H, J=12.3 Hz), 4.38 (d, 1H, J=16.5 Hz), 4.57 (d, 1H, J=16.5 Hz),4.72-4.79 (m, 1H, overlap with HOD), 7.12-7.19 (m, 5H), 7.23 (dd, 2H,J=6, 3 Hz), 7.43 (dd, 2H, J=6, 3 Hz), 7.92 (dd, 1H, J=7.8, 5.7 Hz), 8.16(s, 1H), 8.37 (d, 1H, J=7.2 Hz), 8.76 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O)δ20.43, 21.01, 27.83, 50.22, 56.66, 63.41, 113.62, 120.71, 124.26,126.12, 126.36, 126.78, 130.44, 130.76, 137.01, 139.68, 140.96, 148.27,150.79, 151.60, 152.13. ES-MS m/z 436 (M+H). Anal. Calcd. forC₂₇H₂₅N₅O.2.8HBr.1.9H₂O: C, 46.57; H, 4.57; N, 10.06; Br, 32.13. Found:C, 46.56; H, 4.61; N, 9.73; Br, 32.14.

EXAMPLE: 98

[0612]

AMD9792: Preparation of(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-(4-thiophen-2-yl-benzyl)-amine(hydrobromide salt)

[0613]

[0614] Preparation of 4-thiophen-2-yl-benzaldehyde

[0615] To a stirred degassed solution of 4-bromobenzaldehyde (371 mg,2.00 mmol) and thiophene-2-boronic acid (287 mg, 2.24 mmol) in DME/THF(5 mL, 4:1) were added a 2 M Na₂CO₃ solution (3.0 mL) and Pd(PPh₃)₄ (110mg, 0.095 mmol). The reaction mixture was flushed with argon andmaintained under argon while being heated at 85° C. over 2 days. Themixture was then cooled and diluted with EtOAc (35 mL) and water (30mL). The aqueous layer was washed with EtOAc (2×10 mL) and the combinedorganic extracts dried (Na₂SO₄), filtered and concentrated. Purificationof the resultant oil by column chromatography on silica gel(Hexanes/EtOAc, 4:1) afforded the title compound (293 mg, 78%) as ayellow solid. ¹H NMR (CDCl₃) δ7.14 (dd, 1H, J=5.1, 3.6 Hz), 7.40 (dd,1H, J=5.1, 0.9 Hz), 7.46 (dd, 1H, J=3.6, 0.9 Hz), 7.76 (d, 2H, J=8.4Hz), 7.88 (d, 2H, J=8.4 Hz), 10.00 (s, 1H).

[0616] Using General Procedure B: To a stirred solution of(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(144 mg, 0.52 mmol) and 4-thiophen-2-yl-benzaldehyde (100 mg, 0.53 mmol)in CH₂Cl₂ (5 mL) was added NaBH(OAc)₃ (160 mg, 0.75 mmol) and theresultant mixture was stirred at room temperature overnight.Purification of the crude material by radial chromatography on silicagel gel (2 mm plate, 50:1:1 CH₂Cl₂/MeOH/NH₄OH) afforded the desiredamine (133 mg, 57%) as a yellow foam.

[0617] Using General Procedure D: Conversion of the foam from above (115mg, 0.26 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD9792 (134 mg, 82%) asa yellow solid. ¹H NMR (D₂O) δ1.73-1.77 (m, 1H), 2.00-2.11 (m, 2H),2.24-2.28 (m, 1H), 2.84-2.88 (m, 2H), 3.12 (d, 1H, J=12.3 Hz), 3.45 (d,1H, J=12.3 Hz), 4.20 (d, 1H, J=16.5 Hz), 4.37 (d, 1H, J=16.5 Hz), 4.46(dd, 1H, J=10.2, 6 Hz), 6.85 (d, 2H, J=8.1 Hz), 6.90-6.97 (m, 4H), 7.17(dd, 2H, J=6, 3 Hz), 7.26 (d, 1H, J=5.1 Hz), 7.37 (dd, 2H, J=6, 3 Hz),7.84 (dd, 1H, J=1H, J=7.8, 5.7 Hz), 8.25 (d, 1H, J=7.8 Hz), 8.66 (d, 1H,J=4.7 Hz); ¹³C NMR (D₂O) δ20.39, 20.8 50.08, 56.18, 63.03, 113.58,124.19, 125.34, 126.05, 126.12, 126.63, 128.72, 130.36, 130.67, 133.71,135.22, 139.52, 140.76, 142.84, 148.28, 150.66, 151.42. ES-MS m/z 451(M+H). Anal. Calcd. for C₂₈H₂₆N₄S.2.0HBr.0.9H₂O: C, 53.50; H, 4.78; N,8.91; Br, 25.42 Found: C, 53.65; H, 4.98; N, 8.66; Br, 25.32.

EXAMPLE: 99

[0618]

AMD9778: Preparation of(1H-Benzimidazol-2-ylmethyl)-[4-(2-methyl-2H-tetrazol-5-yl)-benzyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(hydrobromide salt)

[0619] To a stirred solution of 8-amino-5,6,7,8-tetrahydroquinoline (170mg, 1.15 mmol) in dry MeOH (10 mL) was added4-(2-methyl-2H-tetrazol-5-yl)benzaldehyde (prepared as described byBold, G.; Fassler, A.; Capraro, H.-G.; Cozens, R.; Klirnkait, T.;Lazdins, J.; Mestan, J.; Poncioni, B.; Rosel, J.; Stover, D.;Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.; Eschbach, M.;Hurlimann, T.; Masso, E.; Roussel, S.; Ucci-Stoll, K.; Wyss, D.; Lang,M. J. Med. Chem. 1998, 41, 3387-3401) (220 mg, 1.17 mmol) and themixture stirred for 1.5 h at room temperature. The initial yellow-orangesuspension became a dark orange homogeneous solution after this time.The mixture was concentrated in vacuo, analyzed by ¹H NMR andredissolved in MeOH (10 mL). To this solution was added NaBII₄ (85 mg,2.25 mmol) and the mixture stirred for 1 h. The reaction wasconcentrated in vacuo and diluted with CH₂Cl₂ (40 mL) and saturatedaqueous sodium bicarbonate (40 mL). The aqueous phase was washed withCH₂Cl₂ (2×10 mL) and the combined organic extracts dried (Na₂SO₄),filtered and concentrated to afford an orange-brown oil (422 mg) whichwas used without purification in the next reaction.

[0620] Following the general alkylation procedure: To a stirred solutionof the secondary amine from above (205 mg, 0.64 mmol) in CH₃CN (5 mL)was added N′N-diisopropylethylamine (0.23 mL, 1.32 mmol), KI (24 mg,0.14 mmol) and 1-(tert-butoxycarbonyl)-2-(chloromethyl)benzimidazole(165 mg, 0.62 mmol). The mixture was stirred at 60° C. for 3 h.Purification of the resultant brown oil by column chromatography onsilica gel (CH₂Cl₂MeOH, 98:2 then 96:4) followed by radialchromatography on silica gel gel (1 mm plate, CH₂Cl₂/MeOH, 98:2)afforded the desired alkylated amine (44 mg, 43% over 2 steps) as abrown foam.

[0621] Using General Procedure D: Conversion of the foam from above (44mg, 0.08 mmol) to the hydrobromide salt with simultaneous removal of theN-tert-butoxycarbonyl protecting group followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD9778 (45 mg, 87%) asa pale brown solid. ¹H NMR (D₂O) δ1.89-1.94 (m, 1H), 2.19-2.27 (m, 2H),2.43-2.47 (m, 1H), 3.03-3.05 (m, 2H), 3.72 (d, 1H, J=12.6 Hz), 3.84 (d,1H, J=12.6 Hz), 4.35 (s, 2H), 4.43 (d, 1H, J=16.5 Hz), 4.61 (d, 1H,J=16.5 Hz), 4.79-4.89 (m, 1H, overlap with HOD), 7.15 (dd, 2H, J=6, 3Hz), 7.24 (d, 2H, J=8.1 Hz), 7.41 (dd, 2H, J=6, 3 Hz), 7.46 (d, 2H,J=8.1 Hz), 7.95 (dd, 1H, J=7.5, 6.3 Hz), 8.41 (d, 1H, J=8.1 Hz), 8.79(d, 1H, J =5.1 Hz); ¹³C NMR (D₂O) δ20.45, 21.07, 27.86, 40.01, 50.30,56.78, 63.54, 113.67, 125.64, 126.18, 126.32, 126.42, 130.42, 130.91,139.31, 139.75, 141.04, 148.33, 150.77, 151.62, 163.70. ES-MS m/z 451(M+H). Anal. Calcd. for C₂₆H₂₆N₈.2.1HBr.1.5H₂O: C, 48.23; H, 4.84; N,17.31; Br, 25.92. Found: C, 48.49, H, 4.72; N, 17.05; Br, 25.63.

EXAMPLE: 100

[0622]

AMD9715: Preparation of(1H-Benzimidazol-2-ylmethyl)-[4-(5-phenyloxazol-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine

[0623] Preparation of methyl-N-(2-oxo-2-phenylethyl)-terephthalamate

[0624] To a solution of 2-aminoacetophenone (516 mg, 3.0 mmol) andtriethylamine (0.84 mL, 6 mmol) in CH₂Cl₂ (20 mL) at 0° C. was addedmethyl-4-chlorocarbonyl-benzoate (594 mg, 3.0 mmol) dropwise over 10min. The solution was then allowed to warm to room temperature andstirred for 90 min. The solution was washed with saturated aqueous NH₄Cl(20 mL) and the aqueous layer extracted with CH₂Cl₂ (2×10 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered and concentratedin vacuo to afford the desiredmethyl-N-(2-oxo-2-phenylethyl)-terephalamate as pale yellow crystals(835 mg, 94%). ¹H NMR (CDCl₃) δ3.94 (s, 3H), 4.97 (d, 2H, J=5.4 Hz),7.35 (br s, 1H), 7.50 (m, 2H), 7.53 (m, 1H), 7.92 (d, 2H, J=6.6 Hz),8.04 (d, 2H, J=6.6 Hz), 8.11 (d, 2H, J=6.9 Hz).

[0625] Preparation of methyl-4-(5-phenyloxazol-2-yl)-benzoate (asdescribed by Wipf, P., Miller, C.P. J. Org. Chem. 1993, 58, 3604)

[0626] To a solution of triphenylphosphine (524 mg, 2.0 mmol) andtriethylamine (0.56 mL, 4.0 mmol) in CH₂Cl₂ (10 mL) was added iodine(480 mg, 1.9 mmol) and the mixture stirred for 15 min. A solution ofmethyl-N-(2-oxo-2-phenylethyl)-terephalamate (297 mg, 1.0 mmol) inCH₂Cl₂ (5 mL) was added and the resultant mixture was stirred at roomtemperature overnight. The organic phase was washed with 5% aqueoussodium thiosulfate solution (1×15 mL) and saturated NaHCO₃ (1×15 mL) andthen dried Na₂SO₄), filtered and concentrated in vacuo. The resultantoily residue was purified by column chromatography on silica gel (1:1Hexanes/EtOAc) to afford the desired product,methyl-4-(5-phenyloxazol-2-yl)-benzoate, as a yellow oil (69 mg, 24%).¹H NMR (CDCl₃) δ3.86 (s, 3H), 7.20 (m, 1H), 7.23 (t, 1H, J=6.3 Hz), 7.41(s, 1H), 7.64 (m, 2H), 8.04 (m, 4H). ES-MS m/z 280 (M+H).

[0627] To a solution of methyl-4-(5-phenyloxazol-2-yl)-benzoate (56 mg,0.19 mmol) in CH₂Cl₂ (8 mL) at −78° C. was added DIBAL-H (1 mL of a 1.0M solution in CH₂Cl₂, 1.0 mmol) and the solution stirred at −78° C. for90 min. A saturated aqueous solution of sodium potassium tartrate (5 mL)was added to the reaction and the mixture allowed to warm to roomtemperature. The bi-phasic mixture was stirred rapidly for 60 min, thelayers separated and the aqueous layer was extracted with CH₂Cl₂ (2×10mL). The combined organic fractions were dried (Na₂SO₄), filtered andconcentrated in vacuo to afford the desired alcohol,2-(4-hydroxymethylphenyl)-5-phenyloxazole, as a pale yellow oil (46 mg,96%). ¹H NMR (CDCl₃) δ3.41 (t, 1H (OH), J=7.0 Hz), 4.77 (d, 2H, J=7.0Hz), 7.33 (m, 1H), 7.45 (m, 5H), 7.72 (d, 2H, J=6.4 Hz), 8.08 (d, 2H,J=8.1 Hz).

[0628] Following General Procedure C: To a solution of the alcohol fromabove (123 mg, 0.5 mmol) and triethylamine (0.105 mL, 0.75 mmol) inCH₂Cl₂ (8 mL) was added methanesulfonyl chloride (0.05 mL, 0.65 mmol)and the mixture stirred at room temperature for 10 min. The desiredcrude 2-(4-(methanesulfonatomethylphenyl))-5-phenyloxazole was obtainedas a pale yellow oil and used directly without further purification inthe next reaction.

[0629] Following the general alkylation procedure: To a solution of themesylate from above (0.5 mmol) and(1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine(264 mg, 0.7 mmol) in CH₃CN (8 mL) was added N,N-diisopropylethylamine(0.145 mL, 0.8 mmol) and potassium iodide (8 mg, 0.05 mmol) and theresultant mixture heated to 60° C. overnight. The crude residue waspurified by column chromatography on silica gel (CH₂Cl₂/MeOH, 95:5) toafford the desired tertiary amine,(1H-1-tert-butoxycarbonyl-benzimidazol-2-ylmethyl)-[4-(5-phenyloxazol-2-yl)-benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine,as a pale yellow foam (209 mg, 68%). ¹H NMR (CDCl₃) δ1.63 (s, 9H), 2.01(m, 2H), 2.26 (m, 1H), 2.69-2.82 (m, 3H), 3.83 (d, 1H, J=16.1 Hz), 4.05(d, 1H, J=16.1 Hz), 4.32 (m, 1H), 4.69 (s, 2H), 7.12 (m, 1H), 7.15-7.20(m, 3H), 7.33-7.46 (m, 6H), 7.58-7.73 (m, 6H), 8.44 (d, 1H, J=4.9 Hz).ES-MS m/z 612 (M+H).

[0630] Using General Procedure D: Conversion of the foam from above (31mg, 0.05 mmol) to the hydrobromide salt followed by re-precipitation ofthe intermediate solid from methanol/ether gave AMD9715 (28 mg) as awhite solid. ¹H NMR (D₂O) δ1.93 (m, 1H), 2.07 (m, 2H), 2.40 (m, 1H),3.05 (m, 2H), 3.37 (m, 1H), 3.56 (m, 1H), 4.35 (d, 1H, J=16.5 Hz), 4.58(d, 1H, J=16.5 Hz), 4.77 (m, 1H), 7.04 (m, 4H), 7.30-7.37 (m, 6H), 7.49(t, 2H, J=7.2 Hz), 7.64 (m, 2H), 7.92 (dd, 1H, J=7.8, 5.4 Hz), 8.44 (d,1H, J=7.8 Hz), 8.77 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ21.93, 22.13,29.24, 50.89, 57.87, 63.37, 115.13 (2C), 124.32, 125.65 (2C), 127.33,127.43 (2C), 127.83 (2C), 128.11, 130.40, 130.60⁻(2C), 132.33 (2C),133.04, 140.22, 141.84, 144.99, 147.24, 149.33, 153.14, 154.87. ES-MSm/z 512 (M+H). Anal. Calcd. for C₃₃H₂₉N₅O.2.8HBr.2H₂O: C, 51.20; H,4.66; N, 9.05; Br, 28.90. Found: C, 51.16; H, 4.59; N, 8.87; Br, 28.76.

EXAMPLE 101 Inhibition of Chemokine Induced Ca Flux Measured on a FLIPR(Molecular Devices)

[0631] Reagents

[0632] Loading dye: Fluo-3, AM (Molecular Probes F-1241) is dissolved inanhydrous DMSO and stored frozen in aliquots. To increase the solubilityof the dye in the loading medium, 10% (w/v) pluronic acid (MolecularProbes F-127) is added to the Fluo-3 stock solution immediately beforeuse.

[0633] Flux buffer

[0634] HBSS+20 mM Hepes buffer+0.2% BSA, pH 7.4. HBSS 10× [(w/o phenolred and sodium bicarbonate (Gibco 14 065-049)]; Hepes buffer 1M (Gibco15 630-056), BSA (Sigma A3675). The flux buffer is vacuum-filtered andstored refrigerated for a maximum of 5 days. Before use in theexperiment, the buffer is warmed at 37° C. in a waterbath.

[0635] Antagonists

[0636] The test compounds were diluted in flux buffer and added to 4wells of a black microplate (4 parallel measurements per compound). Thefollowing control wells were used: 100% response control (noinhibition), flux buffer was added; 100% inhibition control: chemokinewas added at 5-times the concentration required to induce a Ca flux.

[0637] Preparation of the Agonist (Chemokine) Plate

[0638] The chemokines are diluted in flux buffer to concentrations thatare 4-fold higher than the desired concentrations required forstimulation of the cells (i.e. 2.5 nM for SDF-1α). The chemokines wereadded to untreated 96-well Sero well compound plates (InternationalMedical, Sterilin code 611F96). In the negative control well's (baselinemonitoring), flux buffer is added instead of chemokine. As a positivecontrol to check for dye loading efficiency, 20 μM digitonin (finalconcentration) was also included. The agonist plate was incubated in theFLIPR (37° C.) for 15-30 min.

[0639] Cell Loading Protocol for Measuring Inhibition of SDF-1αInducedCa Flux in SUP-TI cells

[0640] SUP-T1 cells were centrifuged at room temperature (RT) andre-suspended in loading medium (RPMI-1640 containing 2% FBS and 4 μMFluo-3, AM). The cells were incubate at room temperature for 45 min.then washed twice in flux buffer then incubated in flux buffer at roomtemperature for 10 min. The cells were centrifuged and re-suspended influx buffer at a density of 3×10⁶ cells per mL. A 100 μL aliquot of thecell suspension (3×10⁵ cells) was added to each well of a blackmicroplate (Costar 3603), which already contains 50 μL of a solution ofthe test compound (at concentrations that are 3-fold higher than thedesired final compound concentrations). The microplate is then gentlycentrifuged at room temperature. Homogeneous spreading of the cells onthe bottom of the microplate wells was then confirmed with a microscopeand the microplate was incubated in the FLIPR (37° C.) for 10 min. priorto testing.

[0641] Fluorescence Measurements as a Function of Time on the FLIPR

[0642] The FLIPR settings (camera exposure time and laser power) areadjusted to obtain initial fluorescence values between 8,000 and 10,000units. After monitoring a 20 second-baseline, the agonist (chemokine)(50 μL) is added by automatic pipettor with black pipette tips.Fluorescence is measured simultaneously in all wells of the microplateevery 2 seconds (first 2 min) and thereafter every 6 seconds (additional2 min). The average ca-flux measured in each set of 4 identical wells(one test compound) was calculated by the FLIPR software.

[0643] Using the above method, the compounds of the current inventionwere found to inhibit SDF-1α induced Ca flux in SUP-T1 cells between0-100% at a fixed concentration of 5 μg/mL.

EXAMPLE 102 Assay for Inhibition of HIV-1 (NL4.3) Replication in MT-4Cells

[0644] Inhibition of HIV-1 NL4.3 (or III_(B)) replication assays wereperformed as previously described (Bridger et al. J. Med. Chem. 1999,42, 3971-3981; De Clercq et al. Proc. Natl. Acad. Sci, 1992, 89,5286-5290; De Clercq et al. Antimicrob. Agents Chemother. 1994, 38,668-674; Bridger et al. J. Med. Chem. 1995, 38, 366-378). Anti-HIVactivity and cytotoxicity measurements were carried out in parallel.They were based on the viability of MT-4 cells that had been infectedwith HIV in the presence of various concentrations of the testcompounds. After the MT-4 cells were allowed to proliferate for 5 days,the number of viable cells was quantified by a tetrazolium-basedcolorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) procedure in 96-well microtrays. In all of these assays,viral input (viral multiplicity of infection, MOI) was 0.01, or 100times the 50% cell culture infective dose (CCID₅₀). The EC₅₀ was definedas the concentration required to protect 50% of the virus-infected cellsagainst viral cytopathicity.

[0645] When compounds of the current invention were tested forinhibition of HIV-1 NL4.3 or III_(B) replication in MT-4 cells, theywere found to exhibit EC₅₀'s of 0.002-20.0 μg/mL.

[0646] The following compounds of Formula 1 are also prepared in asimilar manner to those set forth above:

[0647](4-Aminomethyl-pyridin-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0648](3-Aminomethyl-pyridin-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0649]1-(3-Aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-ethanone

[0650]1-(5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-ethanone

[0651]3-Aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzenesulfonamide

[0652]5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzenesulfonamide

[0653]N-(3-Aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-hydroxylamine

[0654]N-(5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-hydroxylamine

[0655]N-(3-Aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-O-methyl-hydroxylamine

[0656]N-(5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-O-methyl-hydroxylamine

[0657](4-Aminomethyl-2-methoxymethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0658](2-Aminomethyl-4-methoxymethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0659]N-(2-{[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-formamide

[0660]N-(4-{[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-formamide

[0661]N-(2-{[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-hydroxylamine

[0662](1H-Benzoimidazol-2-ylmethyl)-(2,6-bis-aminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0663](3-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol

[0664](2-Aminomethyl-6-methoxymethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0665]N-(3-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-hydroxylamine

[0666]N-(3-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-O-methyl-hydroxylamine

[0667][2-Aminomethyl-4-(1H-imidazol-2-yl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0668][2-Aminomethyl-4-(1-methyl-1H-imidazol-2-yl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0669][2-Aminomethyl-4-(2H-pyrazol-3-yl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0670][2-Aminomethyl-4-(1-methyl-1H-pyrazol-3-yl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0671][2-Aminomethyl-4-(1H-[1,2,4]triazol-3-yl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0672][2-Aminomethyl-4-(1-methyl-1H-[1,2,4]triazol-3-yl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0673](2-Aminomethyl-4-oxazol-2-yl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0674](2-Aminomethyl-4-furan-2-yl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0675][2-Aminomethyl-4-(tetrahydro-furan-2-yl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0676](2-Aminomethyl-4-thiazol-2-yl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0677][2-Aminomethyl-4-(1H-tetrazol-5-yl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0678][2-Aminomethyl-4-(2-methyl-2H-tetrazol-5-yl)-benzyl]-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0679](2-Aminomethyl-4-pyridin-2-yl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0680](2-Aminomethyl-4-piperidin-2-yl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0681](4-Aminomethyl-3-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol

[0682](2-Aminomethyl-5-methoxymethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0683](4-Aminomethyl-5-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-pyridin-2-yl)-methanol

[0684](4-Aminomethyl-6-methoxymethyl-pyridin-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0685](1H-Benzoimidazol-2-ylmethyl)-(4,6-bis-aminomethyl-pyridin-3-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0686](4-Allylaminomethyl-2-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0687](2-Allylaminomethyl-4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0688](2-Aminomethyl-4-cyclopropylaminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0689](4-Aminomethyl-2-cyclopropylaminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0690](2-Aminomethyl-5-chloro-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0691](2-Aminomethyl-5-bromo-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0692](2-Aminomethyl-5-nitro-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0693]4-Aminomethyl-3-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzonitrile

[0694](5-Amino-2-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0695](2-Aminomethyl-5-trifluoromethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0696](2-Aminomethyl-4-fluoro-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0697](2-Aminomethyl-4-chloro-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0698](2-Aminomethyl-4-bromo-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0699](2-Aminomethyl-4-nitro-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0700]3-Aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzonitrile

[0701](4-Amino-2-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0702](2-Aminomethyl-4-trifluoromethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0703](4-Aminomethyl-2-fluoro-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0704](4-Aminomethyl-2-chloro-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0705](4-Aminomethyl-2-bromo-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0706](4-Aminomethyl-2-nitro-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0707]5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzonitrile

[0708](2-Amino-4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0709](4-Aminomethyl-2-trifluoromethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0710](5-Aminomethyl-thiophen-2-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0711](4-Aminomethyl-thiophen-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0712](4-Aminomethyl-furan-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0713](4-Aminomethyl-1H-pyrrol-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0714](4-Aminomethyl-1-methyl-1H-pyrrol-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0715](4-Aminomethyl-1H-pyrazol-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0716](4-Aminomethyl-1-methyl-1H-pyrazol-3-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0717](3-Aminomethyl-1H-pyrazol-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0718](3-Aminomethyl-1-methyl-1H-pyrazol-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0719](5-Aminomethyl-3H-imidazol-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0720](5-Aminomethyl-1-methyl-1H-imidazol-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0721](5-Aminomethyl-thiazol-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0722](5-Aminomethyl-pyrimidin-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0723](5-Aminomethyl-pyridazin-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0724](5-Allylaminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol

[0725](3-Allylaminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol

[0726](4-Allylaminomethyl-2-methoxymethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0727](3-Allylaminomethyl-4-methoxymethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0728](2-{[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-5-cyclopropylaminomethyl-phenyl)-methanol

[0729](4-{[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-cyclopropylaminomethyl-phenyl)-methanol

[0730](1H-Benzoimidazol-2-ylmethyl)-(4-cyclopropylaminomethyl-2-methoxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0731](1H-Benzoimidazol-2-ylmethyl)-(2-cyclopropylaminomethyl-4-methoxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0732]5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzamide

[0733]5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-N-hydroxy-benzamide

[0734]5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid hydrazide

[0735]5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoicacid

[0736](1H-Benzoimidazol-2-ylmethyl)-(2,4-bis-allylaminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0737](4-Allylaminomethyl-2-cyclopropylaminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0738](2-Allylaminomethyl-4-cyclopropylaminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0739](1H-Benzoimidazol-2-ylmethyl)-(2,4-bis-cyclopropylaminomethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0740](2-Aminomethyl-4-propyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0741](4-Allyl-2-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0742] Acetic acid3-aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzylester

[0743] Acetic acid5-aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzylester

[0744] Acetic acid4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-cyclopropylaminomethyl-benzylester

[0745] Acetic acid2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-5-cyclopropylaminomethyl-benzylester

[0746] Acetic acid3-allylaminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzylester

[0747] Acetic acid5-allylaminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzylester

[0748]5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehydeoxime

[0749]3-Aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehydeoxime

[0750]N-(5-Aminomethyl-2-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-acetamide

[0751]N-(3-Aminomethyl-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-acetamide

[0752]N-(3-(Acetylamino-methyl)-4-{[(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-acetamide

[0753]N-(2-{[(1H-Benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-acetamide

[0754](6-Aminomethyl-1,3-dihydro-isobenzofuranyl-5-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0755](4-Aminomethyl-1,3-dihydro-isobenzofuranyl-5-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

[0756](7-Aminomethyl-1,3-dihydro-isobenzofuran-4-ylmethyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine

1. A compound of the formula

and the salts and prodrug forms thereof Ring A optionally comprises aheteroatom selected from N, O and S; the dotted lines represent optionalunsaturation; R¹, R² and R³ are non-interfering substituents; k is 0-4;l is 0, 1, or 2; X is unsubstituted or substituted C or N; or is O or S;Ar is the residue of an aromatic or heteroarmatic moiety; each n isindependently 0-2; each R is independently H or alkyl (1-6C); j is 0-3;and each Y is independently an optional, non-interfering substituentother than CR₂NR(CR₂)_(n)B where B is aromatic or heteroaromatic orother heterocycle.
 2. The compound of claim 1 wherein each Y isindependently halo, OH, SH, SO, SO₂, or an organic moiety of 1-20C atomsthat does not contain N wherein two such Y may be connected to form afused ring wth Ar, or is selected from the group consisting of—(CR₂)_(m)CN, —(CR₂)_(m)NR⁵ ₂, —(CR₂)_(m)NR(CR₂)_(m)NRR⁴,—(CR₂)_(m)NR(CR₂)_(m)NR(CR₂)_(m)NR⁵ ₂, —(CR₂)_(m)CO(CR₂)_(m)NR⁵ ₂,—(CR₂)_(m)CO(CR₂)_(m)NR(CR₂)_(m)NRR⁴,—(CR₂)_(m)CO(CR₂)_(m)NR(CR₂)_(m)NR(CR₂)_(m)NR⁵ ₂,—(CR₂)_(m)NRCO(CR₂)_(m)NRR⁴, —(CR₂)_(m)NRCO(CR₂)_(m)NR(CR₂)_(m)NR⁵ ₂,—(CR₂)_(m)NRCO(CR₂)_(m)NR(CR₂)_(m)NR(CR₂)_(m)NR(CR₂)_(m)NR⁵ ₂, —CH═N—Z,—(CR₂)_(m)Z, —NR(CR₂)_(m)Z, —(CR₂)_(m)NROH, (CR₂)_(m)CONROH, and(CR₂)_(m)CR═NOH, and those wherein Y comprises guanidino or NHNHR, oramidino; wherein Z is an optionally substituted aromatic orheteroaromatic moiety containing 5-12 ring members; and wherein R is asdefined in claim 1, each m is independently 0-4, and R⁴ and each R⁵ isindependently H, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), or acyl(1-6C), each optionally substituted by one or more nonaromatic,nonheterocyclic substituent(s), and wherein two R⁵ may be connected toform a cyclic amine, optionally containing one or more additionalheteroatoms selected from N, O, and S.
 3. The compound of claim 1wherein ring E is coupled to the remainder of the molecule at position2.
 4. The compound of claim 3 wherein R² and R³ taken together form abenzo substituent.
 5. The compound of claim 4 wherein X is N and ring Ecomprises a pi bond coupled to one N.
 6. The compound of claim 1 whereinring A is saturated and l is
 1. 7. The compound of claim 6 wherein k is0-1.
 8. The compound of claim 7 wherein the ring system which includes Ais tetrahydroquinoline or a substituted form thereof.
 9. The compound ofclaim 1 wherein one of (CR₂)^(a) _(n) and (CR₂)^(b) _(n) is CH₂ and theother is a bond.
 10. The compound of claim 9 wherein (CR₂)^(a) _(n) is abond and (CR₂)^(b) _(n) is CH₂.
 11. The compound of claim 1 wherein atleast one Y is —CH₂NH.2
 12. The compound of claim 1 wherein Ar is theresidue of benzene, benzimazole, benzothiazole, imidazole, oxazole,benztriazole, thiazole, pyridine, or pyrimidine.
 13. A pharmaceuticalcomposition for modulating chemokine receptor activity which comprises atherapeutically effective amount of the compound of any of claims 1-12.14. The use of the compound of any of claims 1-12 for the treatment of acondition mediated by a chemokine receptor.
 15. The use of the compoundof any of claims 1-12 for the treatment of HIV or FIV.